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  • 1. Aahlin, Kristofer
    et al.
    Arvidsson, Per I.
    Huerta, Fernando
    Yngve, Ulrika.
    Preparation of 1-(4-(5-amino-6-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-yl)benzoyl)piperazine derivatives as glycogen synthase kinase 3 inhibitors.2011Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. I [R1 = H or Me], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase 3 (GSK3) inhibitors. Thus, e.g., II was prepd. by cyclization of 3-amino-N-(4-hydroxypyridin-3-yl)pyrazine-2-carboxamide (prepn. given) to get intermediate 3-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-amine, which underwent bromination followed by Suzuki reaction with (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone. Compds. of the invention were tested for their selective inhibitory activity of GSK3β, e.g., II exhibited Ki value of 2.3 nM. The invention compds. are useful for the treatment of cognitive disorders, diabetes, cancer, etc. [on SciFinder(R)]

  • 2.
    Abass, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Syntes av MPro-inhibitor2020Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    December 2019 the new pandemic Covid-19 sweeps the world and impose unmatched challenges on modern humanity, the virus started from Wuhan China and in just a few months the virus had spread to other countries and WHO (World Health Organization) called the disease a pandemic, Covid-19 is caused by the virus SARS-CoV -2 (severe acute respiratory syndrome-Coronavirus2), the virus is largely spread through human-to-human transmission, today more than 263 million people have been infected with the virus while more than 5 million have died.

    SARS-CoV-2 is closely related to other viruses of the genus Betacoronavirus such as bat coronavirus BatCoV RaTG13 (~ 96% sequence identity) and SARS-CoV (~ 80% sequence identity), Coronavirus such as SARS-CoV and SARS-CoV -2 need main protease MPro (3CLPro), MPro is interesting as there are no similar proteases in humans, and it is vital for virus survival as it has essential role in processing and replicating polyproteins of viral RNA.

    ML188 is a SARS-CoV MPro inhibitor, SARS-CoV and SARS-CoV -2 have 80% sequence identity, ML188 can be used as a starting point to analyze and improve MPro inhibitors that can be used against SARS-CoV -2.

    In this study with the use of UGI reaction to synthesized and modified analog to ML188 by exchanging 3-pyridialkarboxaldehyd which is one of the 4 starting material the compound with 4-pyridilkarboxaldehyd. By changing the nitrogen position in the aromatic ring, we want to see if this change can increase or decrease the compound effectiveness and if it has deferent effect on SARS-CoV2.  

    TLC and LC-MS are analysis method that is used to monitor the reaction and determine the purity of the reaction, column chromatography is used to purify the reaction mixture, NMR analysis both proton and carbon NMR is used to confirm the structure of our synthesized product. Result from the LCMS-Analyze showed a clear high peak with the exact mass of our Sought product but it also showed that the purification of the mixture didn’t happen fully thus we still had some impurities in the mixture. both the proton and carbon NMR results data were consistent with our compound structure. Now we need to test if this new compound can result to better inhibition in SARS-CoV2.

  • 3.
    Abd El-Wahed, Aida
    et al.
    Agr Res Ctr, Plant Protect Res Inst, Dept Bee Res, Giza 12627, Egypt.;Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt..
    Yosri, Nermeen
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.;Jiangsu Univ, Sch Food & Biol Engn, Zhenjiang 212013, Jiangsu, Peoples R China..
    Sakr, Hanem H.
    Menoufia Univ, Dept Zool, Fac Sci, Shibin Al Kawm 32512, Egypt..
    Du, Ming
    Dalian Polytech Univ, Sch Food Sci & Technol, Natl Engn Res Ctr Seafood, Dalian 116034, Peoples R China..
    Algethami, Ahmed F. M.
    Alnahalaljwal Fdn Saudi Arabia, POB 617, Al Jumum 21926, Makkah, Saudi Arabia..
    Zhao, Chao
    Fujian Agr & Forestry Univ, Coll Food Sci, Fuzhou 350002, Peoples R China.;Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Control Chinese Med, Taipa, Macao, Peoples R China..
    Abdelazeem, Ahmed H.
    Beni Suef Univ, Dept Med Chem, Fac Pharm, Bani Suwayf 62514, Egypt.;Riyadh Elm Univ, Dept Pharmaceut Sci, Coll Pharm, Riyadh 11681, Saudi Arabia..
    Tahir, Haroon Elrasheid
    Jiangsu Univ, Sch Food & Biol Engn, Zhenjiang 212013, Jiangsu, Peoples R China..
    Masry, Saad H. D.
    Abu Dhabi Food Control Author, Al Ain 52150, U Arab Emirates.;City Sci Res & Technol Applicat, Arid Lands Cultivat Res Inst ALCRI, Dept Plant Protect & Biomol Diag, Alexandria 21934, Egypt..
    Abdel-Daim, Mohamed M.
    Suez Canal Univ, Dept Pharmacol, Fac Vet Med, Ismailia 41522, Egypt..
    Musharraf, Syed Ghulam
    Univ Karachi, HEJ Res Inst Chem, Int Ctr Chem & Biol Sci, Karachi 75270, Pakistan..
    El-Garawani, Islam
    Menoufia Univ, Dept Zool, Fac Sci, Shibin Al Kawm 32512, Egypt..
    Kai, Guoyin
    Zhejiang Chinese Med Univ, Coll Pharm, Lab Med Plant Biotechnol, Hangzhou 310053, Peoples R China..
    Al Naggar, Yahya
    Martin Luther Univ Halle Wittenberg, Inst Biol, Gen Zool, Hoher Weg 8, D-06120 Halle, Saale, Germany.;Tanta Univ, Fac Sci, Zool Dept, Tanta 31527, Egypt..
    Khalifa, Shaden A. M.
    Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, SE-10691 Stockholm, Sweden..
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.;Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, SE-10691 Stockholm, Sweden.;Jiangsu Univ, Int Res Ctr Food Nutr & Safety, Zhenjiang 212013, Jiangsu, Peoples R China..
    Wasp Venom Biochemical Components and Their Potential in Biological Applications and Nanotechnological Interventions2021In: Toxins, E-ISSN 2072-6651, Vol. 13, no 3, article id 206Article, review/survey (Refereed)
    Abstract [en]

    Wasps, members of the order Hymenoptera, are distributed in different parts of the world, including Brazil, Thailand, Japan, Korea, and Argentina. The lifestyles of the wasps are solitary and social. Social wasps use venom as a defensive measure to protect their colonies, whereas solitary wasps use their venom to capture prey. Chemically, wasp venom possesses a wide variety of enzymes, proteins, peptides, volatile compounds, and bioactive constituents, which include phospholipase A2, antigen 5, mastoparan, and decoralin. The bioactive constituents have anticancer, antimicrobial, and anti-inflammatory effects. However, the limited quantities of wasp venom and the scarcity of advanced strategies for the synthesis of wasp venom's bioactive compounds remain a challenge facing the effective usage of wasp venom. Solid-phase peptide synthesis is currently used to prepare wasp venom peptides and their analogs such as mastoparan, anoplin, decoralin, polybia-CP, and polydim-I. The goal of the current review is to highlight the medicinal value of the wasp venom compounds, as well as limitations and possibilities. Wasp venom could be a potential and novel natural source to develop innovative pharmaceuticals and new agents for drug discovery.

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  • 4.
    Abouzayed, Ayman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Theranostic Targeting of GRPR and PSMA in Prostate Cancer2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on five original articles that investigated the theranostics of prostate cancer by gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) targeting. GRPR and PSMA are two extensively evaluated prostate cancer cell markers due to their overexpression in the majority of prostate cancer samples. Theranostic targeting of GRPR and PSMA is an attractive strategy to improve the management of prostate cancer patients.

    Papers I and II focused on the dual targeting of GRPR and PSMA. The effect of linker modification on the affinity for GRPR and PSMA and the pharmacokinetic profile was evaluated. In Paper III, the effect of the GRPR antagonist RM26 conjugation to an albumin-binding domain on the pharmacokinetic profile and its potential use in therapy was investigated. Paper IV focused on developing a GRPR antagonist that was suitable for single-photon emission computed tomography (SPECT) using technetium-99m. In Paper V, the GRPR antagonist developed in Paper IV was translated into a phase I clinical trial to assess safety and dosimetry.

    Modifying the linkers in GRPR and PSMA heterodimers can largely impact the affinity for both targets. This modification influenced the in vivo targeting specificity and biodistribution, with [125I]I-BO530 in Paper I and [111In]In-BQ7812 in Paper II outperforming other analogues. Our findings in Paper III indicated that the conjugation of an albumin-binding domain to RM26 increased the blood concentration of the radiotracer. This increase led to elevated and stable tumour uptake of [111In]In-DOTA-ABD-RM26 after several days of injection. However, [111In]In-DOTA-ABD-RM26 was also increasingly taken up by various healthy organs. The GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26, studied in Paper IV, showed high specificity and affinity for GRPR. This resulted in elevated GRPR-mediated uptake. Additionally, maSSS-PEG2-RM26 could be radiolabelled via a straightforward radiolabelling protocol. Clinical evaluation of [99mTc]Tc-maSSS-PEG2-RM26 in prostate and breast cancer patients (Paper V) demonstrated the safety and tolerability of the radiotracer, with favourable dosimetry and no side effects.

    In conclusion, this thesis evaluated different tools for the theranostic targeting of GRPR and PSMA. The findings warrant further investigation to optimise the reported radiotracers.

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  • 5.
    Acuña, Ulyana Muñoz
    et al.
    Ohio State University, USA.
    Carcache, Peter J Blanco
    Ohio State University, USA.
    Matthew, Susan
    Ohio State University, USA.
    Carcache de Blanco, Esperanza J
    Ohio State University, USA.
    New acyclic bis phenylpropanoid and neolignans, from Myristica fragrans Houtt., exhibiting PARP-1 and NF-κB inhibitory effects.2016In: Food Chemistry, ISSN 0308-8146, E-ISSN 1873-7072, Vol. 202, p. 269-275Article in journal (Refereed)
    Abstract [en]

    The bioassay-guided fractionation of the aril of Myristica fragrans (mace spice) yielded five phenolic compounds, one new acyclic bis phenylpropanoid (1) and four previously known phenolic compounds: compounds (1) (S) 1-(3,4,5-trimethoxyphenyl)-2-(3-methoxy-5-(prop-1-yl) phenyl)-propan-1-ol, (2) benzenemethanol; α-[1-[2,6-dimethoxy-4-(2-propen-1-yl)phenoxy]ethyl]-3,4-dimethoxy-1-acetate, (3) odoratisol A, phenol, 4-[(2S,3S)-2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-propenyl-2-benzofuranyl]-2,6-dimethoxy, (4) 1,3-benzodioxate-5-methanol,α-[1-[2,6-dimethoxy-4-(2-propenyl)phenoxy]ethyl]-acetate, (5) licarin C; benzofuran,2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-yl-2-(3,4,5-trimethoxyphenyl). An NMR tube Mosher ester reaction was used in an approach to characterize and determine the assignment of the absolute configuration of the new isolated chiral alcohol (1). The PARP-1 inhibitory activity was evaluated for compound (1) (IC50=3.04μM), compound (2) (IC50=0.001μM), compound (4) (IC50=22.07μM) and compound (5) (IC50=3.11μM). Furthermore, the isolated secondary metabolites were tested for NF-κB and K-Ras inhibitory activities. When tested in the p65 assay, compounds (2) and (4) displayed potent NF-κB inhibition (IC50=1.5 nM and 3.4nM, respectively).

  • 6.
    Acuña, Ulyana Muñoz
    et al.
    Ohio State University, USA.
    Curley, Robert W
    Ohio State University, USA.
    Fatima, Nighat
    Quaid-i-Azam University, Pakistan;University of Hawaii at Hilo, USA.
    Ahmed, Safia
    Quaid-i-Azam University, Pakistan.
    Chang, Leng Chee
    University of Hawaii at Hilo, USA.
    De Blanco, Esperanza J Carcache
    Ohio State University, USA.
    Differential Effect of Wortmannolone Derivatives on MDA-MB-231 Breast Cancer Cells.2017In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 4, p. 1617-1623Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIM: The survival rate of women diagnosed with triple-negative breast-cancer (TNBC) remains low. Hence, this study aimed at the chemical and biological optimization of furanosteroid derivatives for the treatment of this type of malignancy using TNBC cells.

    MATERIALS AND METHODS: Semi-synthetic analogs of wortmannolone (1-6) that negatively affected the aberrant pathways in tumor cells were evaluated in hormone-independent breast cancer cells using western blot and cell-cycle analysis.

    RESULTS: Wortmannolone derivatization generated NF-ĸB inhibitors as new lead structures for further development. Compound (3) was found to be the most significantly active lead.

    CONCLUSION: Structure-activity analysis in the present study showed that acetylation of the hydroxyl groups and substitution on C3 and C17 of wortmannolone enhanced biological activity. Alpha-substitution of the acetyl group in C3 on ring A (compound 3) resulted in ROS inducing effect; however, presence of an acetyl group in β-position of C3 displayed the highest NF-ĸB p65 inhibitory activity (0.60 μM).

  • 7.
    Adeyemi, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(0)-Catalyzed Synthesis of Spirocycles and Supercritical Chemistry using a Resistively Heated Flow Reactor2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This doctoral thesis focusses on an effective and selective approach to the synthesis of spirocycles using palladium(0)-catalyzed Mizoroki-Heck reactions. In addition, selective and efficient chemistry was highlighted by the design and evaluation of a novel resistively heated system for continuous flow (CF) synthesis for high-temperature and high-pressure applications.

    Paper I described the design and evaluation of a novel resistively heated CF system. The design of a low-cost, simple, robust, and effective CF system involving a resistively heated steel reactor capable of delivering 400 °C and 200 bar was reported. The reactor was evaluated with esterification, transesterification and direct carboxylic acid to nitrile conversions using supercritical ethanol, methanol and acetonitrile respectively. Diels-Alder reactions under neat conditions were also carried out at high temperature and pressure.

    Paper II reported the synthesis of spirooxindoles by a selective application of the palladium(0)-catalyzed Mizoroki-Heck spirocyclization. The precursors for the reaction were synthesized by coupling 2-iodoanilines with esters derived from enantiomerically pure (+)-Vince lactam decorated with the bulky, directing 2,5-dimethylpyrrole protecting group. Ten different spirooxindoles were reported with good yields and high regio- and stereoselectivity. Functionalization of a synthesized spirooxindole was done by a palladium(0)-catalyzed alkoxycarbonylation, followed by selective deprotections.

    In Paper III, ether precursors were synthesized from (+)-Vince lactam, via a Mitsunobu reaction with the corresponding iodophenols. The precursors were later subjected to conditions for intramolecular Mizoroki-Heck reaction. Overall, 12 spiroethers were synthesized in useable yields, regioselectivity up to 98% and with excellent diastereoselectivity (d.e.>98%). Further functionalization to mono-protected rigidified amino acids was also demonstrated.

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  • 8.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wetzel, Alexander
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Brånalt, Jonas
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides2019In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, no 1, p. 82-88Article in journal (Refereed)
    Abstract [en]

    A method for highly regio- and stereoselective intramolecular Mizoroki-Heck 5- exo cyclization of aryl iodides to the corresponding spirooxindoles has been developed. Electron-rich and electron-deficient aryl iodide precursors were selectively ring-closed with high stereoselectivity and good yields. The double-bond position in the cyclopentene ring was controlled by careful choice of reaction conditions. These rare spiro compounds were further functionalized to rigidified unnatural amino acid derivatives by a subsequent gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O - and N -deprotections.

  • 9. Adia, Madina Mohamed
    et al.
    Emami, Seyedeh Noushin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Byamukama, Robert
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Borg-Karlson, Anna-Karin
    Antiplasmodial activity and phytochemical analysis of extracts from selected Ugandan medicinal plants2016In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 186, p. 14-19Article in journal (Refereed)
    Abstract [en]

    Ethnopharmacological relevance: Resistance of the parasites to known antimalarial drugs has provided the necessity to find new drugs from natural products against malaria. The aim of the study was to evaluate the in vitro antiplasmodial activity of some plants used by Traditional Medical Practitioners (TMPs) of Prometra and Rukararwe in malaria treatment in Uganda to provide scientific proof of the efficacies claimed by these Herbalists.

    Materials and methods: The air dried samples of Clerodendrum rotundifolium (leaves), Microglossa pyrifolia (leaves), Momordica foetida (leaves) and Zanthoxylum chalybeum (stem bark) used for malaria treatment by TMPs were successively extracted with ethyl acetate, methanol and water to yield twelve extracts. The extracts were tested against the chloroquine-sensitive (NF54) and chloroquine-resistant (FCR3) Plasmodium falciparum strains in vitro using the micro Mark III test which is based on assessing the inhibition of schizont maturation. A compound A was extracted and purified from the stem bark of Z. chalybeum and its structure was identified and confirmed by spectroscopic methods.

    Results: Most of the extracts tested (92%) showed an antiplasmodial activity with IC50 < 50 mu g/mL. In spite of successive extractions with different solvents, potent anti-plasmodial activity (IC50 < 5 mu g/mL) was observed in the ethyl acetate, methanol and aqueous extracts of M. pyrifolia and C. rotundifolium. Preferential enrichments of activity into water (IC50 < 15 mu g/mL) and Ethyl acetate (IC50 < 5 mu g/mL) were seen in the case of M. foetida and Z chalybeum respectively. The most active extracts were from C rotundifolium and M. pyrifolia with IC50 values less than 2 mu g/mL. Phytochemical analysis of the extracts revealed the presence of saponins, tannins, flavonoids, alkaloids and cardiac glycocides. Fagaramide isolated from Z chalybeum had a higher activity (IC50 2.85 mu g/mL) against the chloroquine-resistant strain than against the chloroquine-senstive (IC50 16.6 mu g/mL) strain used in the study.

    Conclusion: The plant extracts analysed in this study presented an average antiplasmodial activity (58%). This study revealed for the first time the antiplasmodial activity of the plant C. rotundofolium. It's the first time the compound fagaramide (N-isobutyl-3-(3,4-methylene dioxyphenyl) - 2E-propenamide) has been isolated from Z. chalybeum as one of the compounds that contribute to the activity of this plant against P. falciparum.

  • 10.
    Adler, Camille
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland.;Univ Basel, Inst Pharmaceut Technol, Klingelbergstr 50, CH-4056 Basel, Switzerland..
    Schoenenberger, Monica
    Swiss Nanosci Inst, Nanotech Serv Lab, Klingelbergstr 82, CH-4056 Basel, Switzerland..
    Teleki, Alexandra
    DSM Nutr Prod Ltd, R&D Ctr Formulat & Applicat, POB 2676, CH-4002 Basel, Switzerland..
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland..
    Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion2016In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 499, no 1-2, p. 90-100Article in journal (Refereed)
    Abstract [en]

    Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. beta-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity. (C) 2015 Elsevier B.V. All rights reserved.

  • 11.
    Adler, Camille
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland.;Univ Basel, Inst Pharmaceut Technol, CH-4056 Basel, Switzerland..
    Schoenenberger, Monica
    Swiss Nanosci Inst, Nanotech Serv Lab, CH-4056 Basel, Switzerland..
    Teleki, Alexandra
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Leuenberger, Bruno
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland..
    Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix2015In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 115, p. 20-30Article in journal (Refereed)
    Abstract [en]

    Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of beta-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions. (C) 2015 Elsevier B.V. All rights reserved.

  • 12. Adler, Camille
    et al.
    Teleki, Alexandra
    DSM Nutritional Products Ltd., R&D Center Formulation & Application, P. O. Box 2676, 4002 Basel, Switzerland.
    Kuentz, Martin
    Multifractal and mechanical analysis of amorphous solid dispersions2017In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 523, no 1, p. 91-101, article id S0378-5173(17)30191-6Article in journal (Refereed)
    Abstract [en]

    The formulation of lipophilic and hydrophobic compounds is a challenge for the pharmaceutical industry and it requires the development of complex formulations. Our first aim was to investigate hot-melt extrudate microstructures by means of multifractal analysis using scanning electron microscopy imaging. Since the microstructure can affect solid dosage form performance such as mechanical properties, a second objective was to study the influence of the type of adsorbent and of the presence of an amorphous compound on extrudate hardness. β-Carotene (BC) was chosen as poorly water-soluble model compound. Formulations containing a polymer, a lipid and two different silica based inorganic carriers were produced by hot-melt extrusion. Based on scanning electron microscopy/energy dispersive X-ray spectroscopy, the obtained images were analyzed using multifractal formalism. The breaking force of the strands was assessed by a three point bending test. Multifractal analysis and three point bending results showed that the nature of interparticle interactions in the inorganic carrier as well as the presence of amorphous BC had an influence on the microstructure and thus on the mechanical performance. The use of multifractal analysis and the study of the mechanical properties were complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

  • 13. Adler, Camille
    et al.
    Teleki, Alexandra
    Kuentz, Martin
    Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates.2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 2, p. 321-332Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug.

    METHODS: Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior.

    RESULTS: Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important.

    CONCLUSIONS: The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

  • 14.
    Adrian Meredith, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Björklund, Catarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Adolfsson, Hans
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Edlund, Michael
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assayManuscript (preprint) (Other academic)
    Abstract [en]

    In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.

  • 15.
    Adrian Meredith, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Björklund, Catarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Adolfsson, Hans
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jansson, Katarina
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    P2’-truncated BACE-1 inhibitors with a novel hydroxethylene-like core2010In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, no 2, p. 542-554Article in journal (Refereed)
    Abstract [en]

    Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2’ amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-1 IC50 value of 140 nM. The synthesis of these BACE-1 inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.

  • 16.
    Adrian Meredith, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wallberg, Hans
    Vrang, Lotta
    Oscarson, Stefan
    Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
    Parkes, Kevin
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and Synthesis of Novel P2 Substituents in Diol-based HIV Protease Inhibitors2010In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, no 1, p. 160-170Article in journal (Refereed)
    Abstract [en]

    The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val-methylamide P2 motif by appending hydrogen bonding moieties from either the isopropyl side chain or from the methylamide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 µM and 0.33 µM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone x enabling facile modifications of the overall properties in this inhibitor class.

  • 17.
    Afzelius, Lovisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Modelling of Structures and Ligands of CYP2C92004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.

    These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.

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  • 18.
    Ahmed, Laeeq
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Alogheli, Hiba
    Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden..
    McShane, Staffan Arvidsson
    Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden..
    Alvarsson, Jonathan
    Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden..
    Berg, Arvid
    Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden..
    Larsson, Anders
    Uppsala Univ, Dept Cell & Mol Biol, Natl Bioinformat Infrastruct Sweden NBIS, Box 596, S-75124 Uppsala, Sweden..
    Schaal, Wesley
    Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden..
    Laure, Erwin
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Royal Inst Technol KTH, Dept Elect Engn & Computat Sci, Lindstedtsvagen 5, S-10044 Stockholm, Sweden..
    Spjuth, Ola
    Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden..
    Predicting target profiles with confidence as a service using docking scores2020In: Journal of Cheminformatics, E-ISSN 1758-2946, Vol. 12, no 1, article id 62Article in journal (Refereed)
    Abstract [en]

    Background: Identifying and assessing ligand-target binding is a core component in early drug discovery as one or more unwanted interactions may be associated with safety issues. Contributions: We present an open-source, extendable web service for predicting target profiles with confidence using machine learning for a panel of 7 targets, where models are trained on molecular docking scores from a large virtual library. The method uses conformal prediction to produce valid measures of prediction efficiency for a particular confidence level. The service also offers the possibility to dock chemical structures to the panel of targets with QuickVina on individual compound basis. Results: The docking procedure and resulting models were validated by docking well-known inhibitors for each of the 7 targets using QuickVina. The model predictions showed comparable performance to molecular docking scores against an external validation set. The implementation as publicly available microservices on Kubernetes ensures resilience, scalability, and extensibility.

  • 19.
    Ahsan, Ali
    et al.
    Akhtar Saeed Coll Pharmaceut Sci, Lahore, Pakistan..
    Waqar, Muhammad Ahsan
    Lahore Univ Biol & Appl Sci, Fac Pharmaceut Sci, Dept Pharmaceut, Lahore, Pakistan..
    Riaz, Tehseen
    Univ Cent Punjab, Fac Pharmaceut Sci, Lahore, Pakistan..
    Qureshi, Aimon
    Univ Cent Punjab, Fac Pharmaceut Sci, Lahore, Pakistan..
    Butt, Muhammad Hammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Ehsan, Maria
    Akhtar Saeed Coll Pharmaceut Sci, Lahore, Pakistan..
    Munir, Minahal
    Akhtar Saeed Coll Pharmaceut Sci, Lahore, Pakistan..
    Tayyab, Saqiba
    Care Natl Hosp, Riyadh, Saudi Arabia..
    Abid, Syed Zeeshan
    Univ Skövde, Skövde, Sweden..
    Formulation and evaluation of miconazole lipogel for enhanced drug permeation2024In: Pakistan Journal of Pharmaceutical Sciences, ISSN 1011-601X, Vol. 37, no 1, p. 95-105Article in journal (Refereed)
    Abstract [en]

    Hydrophilic drugs could be incorporated into the skin surface by manes of Lipogel. This study aimed to prepare miconazole lipogel with natural ingredients to enhance drug permeability using dimethyl Sulfoxide (DMSO). The miconazole lipogels, A1 (without DMSO) and A2 (with DMSO) were formulated and evaluated for organoleptic evaluation, pH, viscosity, stability studies, freeze -thawing, drug release profile and drug permeation enhancement. Results had stated that prepared lipogel's pH falls within the acceptable range required for topical delivery (4 to 6) while both formulations show good results in organoleptic evaluation. The A2 formulation containing DMSO shows better permeation of miconazole (84.76%) on the artificial skin membrane as compared to A1 lipogel formulation (50.64%). In in -vitro drug release studies, A2 for-mulation showed 87.48% drug release while A1 showed just 60.1% drug release from lipogel. Stability studies were performed on model formulations under environmental conditions and both showed good spreadibility, stable pH, free of grittiness and good consistency in formulation. The results concluded that A2 formulation containing DMSO shows better results as compared to DMSO-free drug lipogel.

  • 20.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chinthakindi, Praveen K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Båhlström, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Palanisamy, Navaneethan
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease2020In: Journal of Biomolecular Structure and Dynamics, ISSN 0739-1102, E-ISSN 1538-0254, Vol. 38, no 18, p. 5526-5536Article in journal (Refereed)
    Abstract [en]

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as 9b, was identified by in silico screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound 9b formed a stable complex with ZIKV protease. Interaction analysis of compound 9b's binding pose from the cluster analysis of MD simulations trajectories predicted that 9b mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound 9b was found to inhibit ZIKV serine protease in vitro with IC50 = 143.25 ± 5.45 µM, in line with the in silico results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds 9b and 86 (a known panflavivirus peptide hybrid with IC50 = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound 86 to be lower than that of 9b, proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound 9b represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.

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  • 21.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pourghasemi Lati, Monireh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Krambrich, Janina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berger, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Turunen, Pauliina
    Science for Life Laboratory, Human Antibody Therapeutics, Drug Discovery and Development Platform, Solna, Sweden.
    Gullberg, Hjalmar
    Science for Life Laboratory, Biochemical and Cellular Assay Facility, Drug Discovery and Development Platform, Department of Biochemistry and Biophysics, Stockholm University, Solna, Stockholm, Sweden.
    Moche, Martin
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden.
    Chinthakindi, Praveen Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Nyman, Tomas
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden..
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Verho, Oscar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical librariesManuscript (preprint) (Other academic)
  • 22.
    Alhalaweh, Amjad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alzghoul, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, no 1, p. 312-317Article in journal (Refereed)
    Abstract [en]

    Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.

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  • 23. Al-Henhena, Nawal
    et al.
    Khalifa, Shaden A. M.
    Ying, Rozaida Poh Yuen
    Hassandarvish, Pouya
    Rouhollahi, Elham
    Al-Wajeeh, Nahla Saeed
    Ali, Habibah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 13312Article in journal (Refereed)
    Abstract [en]

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and beta-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

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  • 24.
    Al-Henhena, Nawal
    et al.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia.;Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Ying, Rozaida Poh Yuen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Ismail, Salmah
    Univ Malaya, Fac Sci, Inst Biol Sci, Kuala Lumpur 50603, Malaysia..
    Hamadi, Riad
    Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Shawter, Abdrabu N.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Idris, Azila Mohd
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Azizan, Ainnul
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Al-Wajeeh, Nahla Saeed
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Abdulla, Mahmood Ameen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo2015In: BMC Complementary and Alternative Medicine, E-ISSN 1472-6882, Vol. 15, article id 419Article in journal (Refereed)
    Abstract [en]

    Background: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. Methods: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. Results: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down-regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. Conclusion: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade.

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  • 25. Al-Henhena, Nawal
    et al.
    Ying, Rozaida Poh Yuen
    Ismail, Salmah
    Najm, Wala
    Khalifa, Shaden A. M.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Abdulla, Mahmood Ameen
    Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, article id e111118Article in journal (Refereed)
    Abstract [en]

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and beta-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

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  • 26.
    Ali, Hala R.
    et al.
    Agr Res Ctr ARC, Egypt.
    Selim, Salah A.
    Cairo Univ, Egypt.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Effects of macrophage polarization on gold nanoparticle-assisted plasmonic photothermal therapy2021In: RSC Advances, E-ISSN 2046-2069, Vol. 11, no 40, p. 25047-25056Article in journal (Refereed)
    Abstract [en]

    Tumor associated macrophages (TAM) are key pathogenic factors in neoplastic diseases. They are known to have plasticity and can polarize into two opposing phenotypes, including the tumoricidal M1 and the protumoral M2 phenotypes with high prevalence of M2-phentoypes in patients with poor prognosis. Strategies for targeting M2-TAM may consequently increase the efficacy of therapeutic strategies for cancer treatment. Gold nanorod-assisted plasmonic photothermal therapy (PPTT) has emerged as a promising treatment for cancer but the effects of macrophage polarization parameters in the performance of this new treatment modality is still unknown. Herein, human monocytic THP-1 cells were polarized into two opposite phenotypic macrophages (M1-TAM and M2-TAM) and their response to PPTT was examined. M2-TAM exhibits a three-fold increase in AuNP uptake compared to M1-TAM. Laser irradiation results in selective killing of pro-tumoral M2-TAM after treatment with AuNPs with limited effects on anti-tumoral M1-TAM. A positive correlation between the expression of CD206 marker and the AuNP uptake may indicate the role of CD206 in facilitating AuNP uptake. Our findings also suggest that the differences in AuNP avidity and uptake between the M1-TAM and M2-TAM phenotypes may be the rationale behind the effectiveness of PPTT in the treatment of solid tumors.

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  • 27.
    Al-ikabi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Developing Inhibitors Against the SARS-CoV-2 Main Protease (MPro)2022Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    COVID-19, the disease caused by the SARS-CoV-2 virus, was first identified in 2019 and spread rapidly, leading to a global pandemic. Over 528,7 million cases have been reported worldwide, alongside 6.2 million deaths. There have been two earlier coronavirus outbreaks; SARS in 2002, and MERS in 2012, but treatment for these diseases remains limited. This shows a clear need for the development of treatments, not only for the current, but also possible future coronavirus outbreaks. While vaccines exist for the current coronavirus, many individuals cannot take them, so the preparation of antiviral agents remains important.

    Small molecule drugs are an attractive alternative for when vaccines are not available or feasible. An appealing target is the coronavirus main protease (MPro). MPro’s biological role is to cleave the viruses two non-functional polyproteins and is therefore important for viral proliferation. Furthermore, it has different selectivity than any known human protease enzymes making it a promising drug target. It was discovered that the Mpro of SARS-CoV and SARS-CoV-2 share 96% sequence identity, making previously explored SARS-CoV Mpro inhibitors a good starting point for drug development.

    ML188 is an Mpro inhibitor that can be synthesized by the Ugi reaction, and a range of analogues have been evaluated in the Moodie group by changing the P1’, P1, P2, and P3 positions. While there were improvements to ML188, there became a problem with the molecules becoming too lipophilic. At the P3 position, there was a plan to include heterocycles to increase polarity and potency, but the corresponding isocyanides needed for the Ugi reaction proved difficult to synthesize. The strategy in this project was to use a dummy isocyanide, which could be removed after the Ugi reaction to unveil a carboxylic acid group at P3. Then standard amide couplings could be used to explore previously inaccessible P3 analogues. Due to the unexplored nature of the chemistry of the synthesis, an optimization process was used at every step. Different conditions, including solvents, temperature, reagent, work up conditions, and reaction durations were investigated. Inividual reactions were evaluated and compared by documenting yields and comparing purity in NMR and LC-MS.

    The first main target for the optimization was the cleavable ugi product. The required dummy 6-bromo-2-isocyanopyridine was made in two steps. First by N-formylation, and then dehydration with POCl3 to create the isocyanide group. The Ugi reaction was then conducted to make an analogue with the same P1, P1l and P2 groups as ML188. During the optimization of this reaction, it was found that using the solvent 2,2,2-trifluoroethanol resulted in a productof increased purity. Cleavage of the dummy group was performed with different reaction durations and temperatures, and a range of purification conditions were explored. This method provides high purity carboxylic acid that will be used for amide coupling to create new P3 analogues. Developing methodology to alter the largely unexplored P3 group of ML188 is a crucial step to synthesize new ML188 analogues. This work could potentially lead to drugs with stronger inhibitory effects on Mpro and therefore coronavirus viralproliferation. Because of the similarities between coronavirus Mpro’s, these compounds may also be effective against future coronaviruses.

  • 28.
    AL-Jabiry, Ekram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Syntetisering av en ny MALDI-MS matris med användning av Suzukikopplingsreaktion2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
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  • 29.
    Al-kaisy, Muhammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Matthias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Persson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Petterson Bergstrand, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sterby, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wang, Pin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    En förstudie för framtagning av HIV-proteashämmare: Me-too läkemedel till indinavir2012Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The purpose of this report was to develop theoretical analogues of indinavir that ispredicted to bind well to HIV-I protease, wild type and mutants. These analogues aremeant for experimental testing by enzyme assay and cell-based β-galactosidase activityassay to see if they have potential to be new protease inhibitors for HIV. 80 analoguesprovided by the company Syntesdesign AB were analyzed with the software Glide.This was done to find out the binding affinities to HIV-I protease and some of its mostcommon mutations. The results were analyzed to see how different structuralelements contributed to high affinity. 48 new analogues were suggested and alsoanalyzed based on the results of the computer simulations. The 30 analogues with thepredicted highest affinity to the wild type protease and the mutations were selectedand ranked. All but one of these analogues were predicted to have better binding tothe protease than Indinavir.

  • 30.
    Alkhouri, Nadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Förståelse av peptidläkemedelsabsorption genom In-vitro studier: En resa genom gelstrukturer och molekylära interaktioner.2024Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Subcutaneous drug administration is one of the most common routes for drug delivery today, offering simplicity and reduced discomfort compared to other injection methods. However, challenges such as variable absorption and bioavailability exist, influenced by factors including the site of administration, drug properties and formulation. This study investigates how molecular weight and charge affect the absorption of subcutaneous peptide drugs. Gel models were created to simulate the extracellular matrix, enabling the study of concentration differences within and outside the matrix under equilibrium conditions. UV-spectroscopy was employed to quantify drug concentrations and distribution. The results demonstrated well-defined linear regressions, confirming the reliability of the chosen methods.The study reveals that larger molecules exhibit decreased absorption, potentially due to adsorption and gel network hindrance. Moreover, an increase in positive charges correlates with enhanced distribution coefficients, particularly evident in negatively charged gels. Understanding these factors is crucial for optimizing drug absorption and bioavailability, offering insights for future drug development and personalized treatments.

  • 31.
    Alniss, Hasan Y.
    et al.
    Univ Sharjah, Coll Pharm, POB 27272, Sharjah, U Arab Emirates;Univ Sharjah, Sharjah Inst Med Res, POB 27272, Sharjah, U Arab Emirates.
    Witzel, Ini-Isabee
    New York Univ Abu Dhabi, Core Technol Platform, POB 129188, Abu Dhabi, U Arab Emirates.
    Semreen, Mohammad H.
    Univ Sharjah, Coll Pharm, POB 27272, Sharjah, U Arab Emirates;Univ Sharjah, Sharjah Inst Med Res, POB 27272, Sharjah, U Arab Emirates.
    Panda, Pritam Kumar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Mishra, Yogendra Kumar
    Univ Kiel, Inst Mat Sci, Funct Nanomat, Kaiserstr 2, D-24143 Kiel, Germany;Univ Southern Denmark, NanoSYD, Mads Clausen Inst, Alsion 2, DK-6400 Sonderborg, Denmark.
    Ahuja, Rajeev
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Royal Inst Technol KTH, Dept Mat & Engn, SE-10044 Stockholm, Sweden.
    Parkinson, John A.
    Univ Strathclyde, Dept Pure & Appl Chem, WestCHEM, 295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland.
    Investigation of the Factors That Dictate the Preferred Orientation of Lexitropsins in the Minor Groove of DNA2019In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 22, p. 10423-10440Article in journal (Refereed)
    Abstract [en]

    Lexitropsins are small molecules that bind to the minor groove of DNA as antiparallel dimers in a specific orientation. These molecules have shown therapeutic potential in the treatment of several diseases; however, the development of these molecules to target particular genes requires revealing the factors that dictate their preferred orientation in the minor grooves, which to date have not been investigated. In this study, a distinct structure (thzC) was carefully designed as an analog of a well-characterized lexitropsin (thzA) to reveal the factors that dictate the preferred binding orientation. Comparative evaluations of the biophysical and molecular modeling results of both compounds showed that the position of the dimethylaminopropyl group and the orientation of the amide links of the ligand with respect to the 5'-3'-ends; dictate the preferred orientation of lexitropsins in the minor grooves. These findings could be useful in the design of novel lexitropsins to selectively target specific genes.

  • 32. Alogheli, Hiba
    A study of conformational energy penalties of protein-bound macrocyclesIn: Article in journal (Refereed)
  • 33.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Computational tools are utilized in the drug discovery process to discover, design, and optimize new therapeutics. One important approach is structure-based drug design which relies on knowledge about the 3D structure of the biological target. The first part of this work focuses on applying structure-based drug design for binding mode prediction of HCV NS3 protease inhibitors. The NS3 protease is a challenging target from a computational perspective as it contains an extended binding site. Binding mode predictions were performed for various classes of new acyclic and macrocyclic HCV NS3 protease inhibitors and was used in the design of new inhibitors. None of the synthetized inhibitors have been co-crystallized yet, which has made the evaluation of the suggested binding mode predictions challenging.

    Macrocycles are an interesting compound class in drug discovery due to their unique structural architecture, which can enable access to new chemical space. Macrocycles can successfully modulate difficult therapeutic targets, as exemplified in the development of protease inhibitors. Furthermore they can improve drug-like properties, such as cell permeability and bioavailability. The second part of this thesis focuses on macrocycles from a computational point of view. A data set of 47 clinically relevant macrocycles was compiled and used in these studies. First, two different docking protocols rigid docking of pre-generated conformers and flexible docking in Glide were evaluated and compared. The results showed that flexible docking in Glide was sufficient for docking of macrocycles with respect to accuracy and speed.

    The aim of the second study was to evaluate and compare the performance of the more general conformational analysis tools, MCMM and MTLMOD, with the recently developed macrocycle-specialized conformational sampling tools, Prime-MCS and MMBS. In most cases, the general conformational analysis tools (with enhanced parameter settings) performed equally well as compared to the macrocycle-specialized conformational sampling techniques. However, MMBS was superior at locating the global energy minimum conformation.

    Finally, calculation of the conformational energy penalty of protein-bound macrocycles was performed. The macrocycle data set was complemented with linear analogues that are similar either with respect to physicochemical properties or 2D fingerprints. The conformational energy penalties of these linear analogues were calculated and compared to the conformational energy penalties of the macrocycles. The complete data set of macrocycles and non-macrocycles in this study differ from previously published work addressing conformational energy penalties, since it covers a more extended area of chemical space. Furthermore, there was a weak correlation between the calculated conformational energy penalties and the flexibility of the structures.

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  • 34.
    Alogheli, Hiba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Olanders, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Anders, Karlén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide2017In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed)
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

  • 35.
    Alsaleem, Hind
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Syntes av 2-tert-butyl imidazol- ett intermediat i syntesen av en Lol-CDE-inhibitor2023Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakterier, encelliga organismer som finns överallt omkring oss, kan vara vänligt sinnade, som de som hjälper till med matsmältning och stärker immunförsvaret. De kan också vara farliga, och detta arbete fokuserar på de farliga gramnegativa bakterierna och deras skyddande yttre membran.

    Historien om antibiotika börjar med upptäckten av penicillin av Alexander Fleming 1928 och revolutionerade medicin. Dock har bakterier med tiden utvecklat antibiotikaresistens, vilket skapar ett globalt problem. Därför behövs nya antibiotika och innovativ forskning, som kan inleda till nya måltavlor där Lol-proteiner och deras roll i gramnegativa bakteriers överlevnad kan möjligtvis leda till en ny måltavla.

    I detta arbete utforskas syntesen av 2-tert-butylimidazol, en nyckelkomponent i utvecklingen av en Lol-CDE-hämmare. Syftet är att undersöka dess struktur och funktion i jämförelse med andra föreningar och dess roll i inhibitorns framställning. Framgångsrik syntes av 2-tert-butylimidazol skulle vara ett stort steg mot önskad hämning av Lol-CDE-proteinet.

    I detta arbete framställdes 2-tert-butylimidazol omfattar en Debus-Radzszewski-reaktion enligt en tidigare metod där en blandning av ammoniaklösning (25%), tert-butyl-aldehyd och glyoxallösning (40%) användes. För att övervaka reaktionens framsteg användes tunnskiktskromatografi (TLC), och när reaktionen var avslutad filtrerades blandningen genom vakuumsug. Produktens struktur och renhet analyserades med hjälp av gaskromatografi-masspektrometri (GC-MS), vätskekromatografi-masspektrometri (LC-MS) och kärnmagnetisk resonansspektroskopi (NMR). Kolonnkromatografi användes sedan för att rena produkten. Nästan 2 gram 2-tert-butyl imidazol framställdes, och produktens struktur och renhet bekräftades genom olika metoder som analyserade molekylens massa och atommiljö. Denna molekyl kommer att användas i framtiden för att skapa en ny inhibitor för Lol-CDE, och dess struktur-aktivitetsförhållande kommer att utforskas närmare. 

    Sammanfattningsvis representerar den framgångsrika syntesen av 2-tert-butylimidazol ett viktigt steg mot utvecklingen av en Lol-CDE-hämmare. Arbetet belyser de utmaningar som är förknippade med syntes av komplexa molekyler och betonar vikten av analytiska tekniker för validering av produkten. Denna forskning bidrar till ansträngningarna att bekämpa antibiotikaresistens och upptäcka nya strategier för behandling av bakteriella infektioner.

  • 36.
    Alterman, Mathias
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Design and synthesis of HIV-1 protease inhibitors2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). The C2-symmetric HIV-1 protease is one of the prime targets for chemotherapy in the treatment of the HIV infection. Inhibition of HIV-1 protease leads to immature and non-infectious viral particles. Design and synthesis of a number of C2-symmetrical C-terminal duplicated HIV-1 protease inhibitors and subsequent biological evaluation is presented in this thesis.

    A versatile three step synthetic route has been developed using a carbohydrate as an inexpensive chiral starting material thus allowing inhibitors with the desired stereochemistry to be obtained. By this efficient method a series of tailor-made P2/P2' modified inhibitors were synthesized, and these were evaluated on purified HIV-1 protease and in HIV-1 infected cell assays. Highly active HIV-1 protease inhibitors were identified among the tested compounds. Analyses of the X-ray crystal structures of two of the most active compounds, as complexes with the protease, guided the further design of P1/P1' elongated inhibitors. Substitutions in the para-position of the P1/P1' benzyl groups were promoted efficiently by microwave-irradiated of palladium-catalyzed reactions. Particular modifications in the P1/P1' region of the inhibitors resulted in a 40-fold increase of the anti-viral activity on HIV-1 infected cells. Furthermore, a fast, efficient, and general one-pot microwave enhanced synthesis protocol for transformations of organo-bromides to tetrazoles was developed and applied on the inhibitor scaffold. Attachment of linker molecules to the P1/P1' benzyl groups of one inhibitor was used to develop of sensitivity enhancer tools in surface plasmon resonance biosensor assays. These new assays enable the evaluation of low-molecular weight compounds as HIV-1 protease inhibitors.

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  • 37.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Univ Autonoma Barcelona, Spain.
    Lopez-Bejar, Manel
    Univ Autonoma Barcelona, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    The risk of using monoclonal or polyclonal commercial antibodies: controversial results on porcine sperm CD44 receptor identification2019In: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 54, no 4, p. 733-737Article in journal (Refereed)
    Abstract [en]

    Presence of the hyaluronan (hyaluronic acid, HA) receptor CD44 on spermatozoa has been difficult to pursue, mostly obeying to the use of different commercial mono- and/or polyclonal antibodies, often lacking proper controls. Here, we describe how the presence (Western blotting) and specific location (immunocytochemistry) of the CD44 receptor differs in ejaculated pig spermatozoa depending on the type of antibody and protocol used. While we were able to detect binding to spermatozoa and mark its presence in the sperm membrane, the use of blocking peptides clearly indicated that only the monoclonal antibody could confirm the specific presence and location of the CD44 receptor, whereas the polyclonal antibody was detecting multiple presumed CD44 isoforms or degraded proteins thus proving unspecific. These results call for strict protocols when attempting immunological determination of sperm membrane receptors.

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  • 38.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. CSIC, Spain.
    Roca, Jordi
    Univ Murcia, Spain.
    Martinez, Emilio A.
    Univ Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Mating modifies the expression of crucial oxidative-reductive transcripts in the pig oviductal sperm reservoir: is the female ensuring sperm survival?2023In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 14, article id 1042176Article in journal (Refereed)
    Abstract [en]

    BackgroundMating induces large changes in the female genital tract, warranting female homeostasis and immune preparation for pregnancy, including the preservation of crucial oxidative status among its pathways. Being highly susceptible to oxidative stress, sperm survival and preserved function depend on the seminal plasma, a protection that is removed during sperm handling but also after mating when spermatozoa enter the oviduct. Therefore, it is pertinent to consider that the female sperm reservoir takes up this protection, providing a suitable environment for sperm viability. These aspects have not been explored despite the increasing strategies in modulating the female status through diet control and nutritional supplementation. AimsTo test the hypothesis that mating modifies the expression of crucial oxidative-reductive transcripts across the entire pig female genital tract (cervix to infundibulum) and, particularly in the sperm reservoir at the utero-tubal junction, before ovulation, a period dominated by estrogen stimulation of ovarian as well as of seminal origin. MethodsThe differential expression of estrogen (ER) and progesterone (PR) receptors and of 59 oxidative-reductive transcripts were studied using a species-specific microarray platform, in specific segments of the peri-ovulatory sow reproductive tract in response to mating. ResultsMating induced changes along the entire tract, with a conspicuous downregulation of both ER and PR and an upregulation of superoxide dismutase 1 (SOD1), glutaredoxin (GLRX3), and peroxiredoxin 1 and 3 (PRDX1, PRDX3), among other NADH Dehydrogenase Ubiquinone Flavoproteins, in the distal uterus segment. These changes perhaps helped prevent oxidative stress in the area adjacent to the sperm reservoir at the utero-tubal junction. Concomitantly, there were a downregulation of catalase (CAT) and NADH dehydrogenase (ubiquinone) oxidoreductases 1 beta subcomplex, subunit 1 (NDUFB1) in the utero-tubal junction alongside an overall downregulation of CAT, SOD1, and PRDX3 in the ampullar and infundibulum segments. ConclusionsNatural mating is an inducer of changes in the expression of female genes commanding antioxidant enzymes relevant for sperm survival during sperm transport, under predominant estrogen influence through the bloodstream and semen. The findings could contribute to the design of new therapeutics for the female to improve oxidative-reductive balance.

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  • 39.
    Al-Wendawi, Amena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis of matrices for MALDI spectrometry2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a disorder in the cells that produce dopamine. It mostly affects people older than 60 years old and more common for men than women. Disturbances in these signal transmissions lead to progressive motor impairment such as reduced mobility, dyskinesia, and tremors. 

    Matrix-assisted laser desorption ionization (MALDI) has become one of the most important "soft" mass spectrometry methods to analyze macromolecules such as proteins, polymers, lipids, and peptides in tissue. MALDI is a suitable method for label-free mapping of molecules in tissue samples found in the brain and lung slices. Several research questions can be explored in Parkinson's diseases using MALDI MS to analyze the localization of new PD drugs in the brain. 

    In MALDI MS, the choice of the matrix has a major role in the detection of the analyte. The matrix has the function of absorbing the laser UV light, which protects the integrity of the analysis and helps ionization. Important matrix properties include the ability to absorb the specific wavelength from the laser, maintain stability under vacuum conditions, analyte ionization, and prevent the formation of cluster ions. There are two types of matrices, regular and reactive matrices and recent development has a strong focus on reactive matrices because of their advantages in small molecule detection. 

     

    The purpose of this work to increase sensitivity in MALDI MS by synthesizing three matrices that can either react with carbonyl, aldehyde, or alkene. The matrices were synthesized by using Suzuki coupling reaction, Wittig reaction and methylation. The purpose of this work was achieved, and the three matrices have been synthesized and purified for testing in MALDI MS. 

     The result from MALDI MS will show if these matrices have resolved the problem of low sensitivity. And another possible future work is to test the Wittig reaction on the ketone product to compare this one to aldehyde.

     

     

     

  • 40.
    Amini, Ahmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Analysis of Caffeine in Dietary Products by Multiple Injection Capillary Electrophoresis2012In: Caffeine: Chemistry, Analysis, Function and Effects / [ed] Victor R Preedy, London: Royal Society of Chemistry, 2012, p. 154-178Chapter in book (Refereed)
  • 41.
    Amini, Ahmad
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Enantiomeric separation by capillary electrophoresis: With special emphasis on the partial filling technique1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Capillary electrophoresis as a powerful separation technique was employed for resolution of racemic drugs. Taurodeoxycholate (TDC), different cyclodextrins and α1- acid glycoprotein (AGP) were dissolved in the background electrolyte at low pH (3.0 to 4.0 ) as chiral selectors.

    Enantioresolutions were based on the principle of micellar electrokinetic chromatography, inclusion complexation and affinity interactions between the enantiomers and TDC, cyclodextrins and AGP, respectively.

    The influence of chiral selector concentration and type, temperature and addition of organic modifiers on enantioselectivity were studied. The temperature was found to be an important factor for regulation of the enantioresolution.

    In order to avoid UV-absorbance interferences between AGP as a UV-absorbing chiral selector as well as to reduce consumption of chiral selector solution, the partial filling technique (PFT) was employed. The technique was developed and equations describing the feature of the technique as an efficient separation mode in CE was presented. Parameters such as applied plug length (PLapp) and effective plug length (PLeff) were determined. Equations expressing the relation between the PLeff and selectivity and resolution factors were developed.

    The PFT was used for determination of association constants between AGP as chiral selector and the enantiomers of disopyramide and remoxipride. The association was strongly temperature dependent, and a maximum in binding was observed at 25°C. The PFT was found to be a very convenient approach for measurement of association constants.

    To verity the above mentioned technique for evaluation of binding constants, the association constants between methyl-β-cyclodextrin and the enantiomers of orciprenaline at different chiral selector concentrations were measured and compared with the data obtained by the conventional technique. The results illustrate the reliability of the system based on the PFT.

  • 42.
    Amini, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lodén, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Principles for different modes of multiple-injection CZE2008In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, no 19, p. 3952-3958Article in journal (Refereed)
    Abstract [en]

    This paper introduces four different modes of multiple-injection CZE (MICZE). The validity of these MICZE models was evaluated by the experimental data. Prior to the application of MICZE, the electrophoretic conditions are developed in the single-injection mode by adjusting different experimental parameters such as pH, type and concentration of buffer additives and temperature. Based on the migration time difference (tmig) between the analyte and the internal standard or injection marker, one or more MICZE modes can be employed. The injection marker is added to the sample to compensate for injection-volume fluctuations. The inter-plug distance is regulated by applying an electrical field over the capillary for a short period of time between each injection. After the final injection, the separation is completed by electrophoresis for a time period corresponding to that in the single-injection mode

  • 43.
    Amirhosseini, Mehdi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bernhardsson, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Lång, Pernilla
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Andersson, Göran
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Flygare, Johan
    Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden..
    Fahlgren, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.2019In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, no 9, p. 16503-16516Article in journal (Refereed)
    Abstract [en]

    Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8-and its paralog CDK19-have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8/19 inhibitor affects cancellous bone healing in rats. CDK8/19 inhibitors did not alter the proliferation of neither mouse bone marrow-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor κΒ (NF-κB) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-κB, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.

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  • 44.
    An, Junxue
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Forchheimer, Daniel
    KTH Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Savmarker, Jonas
    Orexo AB, Pharmaceut Dev, Uppsala, Sweden..
    Brulls, Mikael
    AstraZeneca, Early Prod Dev & Mfg Pharmaceut Sci, R&D, Gothenburg, Sweden..
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nanoscale characterization of PEGylated phospholipid coatings formed by spray drying on silica microparticles2020In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 577, p. 92-100Article in journal (Refereed)
    Abstract [en]

    Phospholipids constitute biocompatible and safe excipients for pulmonary drug delivery. They can retard the drug release and, when PEGylated, also prolong the residence time in the lung. The aim of this work was to assess the structure and coherence of phospholipid coatings formed by spray drying on hydrophilic surfaces (silica microparticles) on the nanoscale and, in particular, the effect of addition of PEGylated lipids thereon. Scanning electron microscopy showed the presence of nanoparticles of varying sizes on the microparticles with different PEGylated lipid concentrations. Atomic force microscopy confirmed the presence of a lipid coating on the spray-dried microparticles. It also revealed that the lipid-coated microparticles without PEGylated lipids had a rather homogenous coating whereas those with PEGylated lipids had a very heterogeneous coating with defects, which was corroborated by confocal laser scanning microscopy. All coated microparticles had good dispersibility without agglomerate formation, as indicated by particle size measurements. This study has demonstrated that coherent coatings of phospholipids on hydrophilic surfaces can be obtained by spray drying. However, the incorporation of PEGylated lipids in a one-step spray-drying process to prepare lipid coated microparticles with both controlled-release and stealth properties is very challenging. (C) 2020 The Authors. Published by Elsevier Inc.

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  • 45. Andersen, Thomas L.
    et al.
    Friis, Stig D.
    Audrain, Helene
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Skrydstrup, Troels
    Efficient C-11-Carbonylation of Isolated Aryl Palladium Complexes for PET: Application to Challenging Radiopharmaceutical Synthesis2015In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 4, p. 1548-1555Article in journal (Refereed)
    Abstract [en]

    We describe the successful implementation of palladium-aryl oxidative addition complexes as stoichiometric reagents in carbonylation reactions with (CO)-C-11 to produce structurally challenging, pharmaceutically relevant compounds. This method enables the first C-11-carbonyl labeling of an approved PET tracer, [C-11]raclopride, for the dopamine D2/D3 receptor by carbonylation with excellent radiochemical purity and yield. Two other molecules, [C-11]olaparib and [C-11]JNJ 31020028, were efficiently labeled in this manner. The technique distinguishes itself from existing methods by the markedly improved purity profiles of the tracer molecules produced and provides access to complex structures in synthetically useful yields, hereby offering a viable alternative to other C-11-labeling strategies.

  • 46.
    Anderson, Orlagh
    et al.
    Univ Durham, Dept Biosci, Stockton Rd, Durham DH1 3LE, England.;Univ Durham, Ctr Global Infect Dis, Stockton Rd, Durham DH1 3LE, England..
    Beckett, Joseph
    Univ Durham, Dept Biosci, Stockton Rd, Durham DH1 3LE, England.;Univ Durham, Ctr Global Infect Dis, Stockton Rd, Durham DH1 3LE, England..
    Briggs, Carla C.
    Univ Durham, Dept Biosci, Stockton Rd, Durham DH1 3LE, England.;Univ Durham, Ctr Global Infect Dis, Stockton Rd, Durham DH1 3LE, England..
    Natrass, Liam A.
    Univ Durham, Dept Biosci, Stockton Rd, Durham DH1 3LE, England.;Univ Durham, Ctr Global Infect Dis, Stockton Rd, Durham DH1 3LE, England.;Univ Durham, Dept Chem, Stockton Rd, Durham DH1 3LE, England..
    Cranston, Charles F.
    Univ Durham, Dept Biosci, Stockton Rd, Durham DH1 3LE, England.;Univ Durham, Ctr Global Infect Dis, Stockton Rd, Durham DH1 3LE, England..
    Wilkinson, Elizabeth J.
    Bangor Univ, Sch Nat Sci, Dept Chem, Bangor LL57 2UW, Gwynedd, Wales..
    Owen, Jack H.
    Bangor Univ, Sch Nat Sci, Dept Chem, Bangor LL57 2UW, Gwynedd, Wales..
    Williams, Rhodri Mir
    Bangor Univ, Sch Nat Sci, Dept Chem, Bangor LL57 2UW, Gwynedd, Wales..
    Loukaidis, Angelos
    Bangor Univ, Sch Nat Sci, Dept Chem, Bangor LL57 2UW, Gwynedd, Wales..
    Bouillon, Marc E.
    Bangor Univ, Sch Nat Sci, Dept Chem, Bangor LL57 2UW, Gwynedd, Wales..
    Pritchard, Deiniol
    Bangor Univ, Naturiol Bangor Ltd, Alun Roberts Bldg, Bangor LL57 2UW, Gwynedd, Wales..
    Lahmann, Martina
    Bangor Univ, Sch Nat Sci, Dept Chem, Bangor LL57 2UW, Gwynedd, Wales..
    Baird, Mark S.
    Bangor Univ, Naturiol Bangor Ltd, Alun Roberts Bldg, Bangor LL57 2UW, Gwynedd, Wales..
    Denny, Paul W.
    Univ Durham, Dept Biosci, Stockton Rd, Durham DH1 3LE, England.;Univ Durham, Ctr Global Infect Dis, Stockton Rd, Durham DH1 3LE, England..
    An investigation of the antileishmanial properties of semi-synthetic saponins2020In: RSC MEDICINAL CHEMISTRY, ISSN 2632-8682, Vol. 11, no 7, p. 833-842Article in journal (Refereed)
    Abstract [en]

    Leishmaniasis is a neglected tropical disease caused by insect-vector borne protozoan parasites of the,Leishmania species. Whilst infection threatens and affects millions of the global poor, vaccines are absent and drug therapy limited. Extensive efforts have recently been made to discover new leads from small molecule synthetic compound libraries held by industry; however, the number of new chemical entities identified and entering development as anti-leishmanials has been very low. This has led to increased interest in the possibility of discovering naturally derived compounds with potent antileishmanial activity which may be developed towards clinical applications. Plant-derived triterpenoid and steroidal saponins have long been considered as anti-microbials and here we describe an investigation of a library of 137 natural (9) and semi-synthetic saponins (128) for activity againstLeishmania mexicana, a causative agent of cutaneous leishmaniasis. The triterpenoid sapogenin, hederagenin, readily obtained in large quantities fromHedera helix(common ivy), was converted into a range of 128 derivatives. These semi-synthetic compounds, as well as saponins isolated from ivy, were examined with a phenotypic screening approach to identify potent and selective anti-leishmanial hits. This led to the identification of 12 compounds, including the natural saponin gypsogenin, demonstrating high potency (ED50< 10.5 mu M) against axenicL. mexicanaamastigotes, the mammalian pathogenic form. One of these, hederagenin disuccinate, was sufficiently non-toxic to the macrophage host cell to facilitate further analyses, selectivity index (SI) > 10. Whilst this was not active in an infected cell model, the anti-leishmanial properties of hederagenin-derivatives have been demonstrated, and the possibility of improving the selectivity of natural hederagenin through chemical modification has been established.

  • 47.
    Andersson, C. David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hillgren, J. Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry and Molecular Biology - Medicinal Chemistry, University of Gothenburg.
    Lindgren, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Laboratories for Chemical Biology Umeå, Umeå University.
    Akfur, Christine
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase2015In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, no 3, p. 199-215Article in journal (Refereed)
    Abstract [en]

    Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.

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  • 48.
    Andersson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Multivariate design of molecular docking experiments: An investigation of protein-ligand interactions2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    To be able to make informed descicions regarding the research of new drug molecules (ligands), it is crucial to have access to information regarding the chemical interaction between the drug and its biological target (protein). Computer-based methods have a given role in drug research today and, by using methods such as molecular docking, it is possible to investigate the way in which ligands and proteins interact. Despite the acceleration in computer power experienced in the last decades many problems persist in modelling these complicated interactions. The main objective of this thesis was to investigate and improve molecular modelling methods aimed to estimate protein-ligand binding. In order to do so, we have utilised chemometric tools, e.g. design of experiments (DoE) and principal component analysis (PCA), in the field of molecular modelling. More specifically, molecular docking was investigated as a tool for reproduction of ligand poses in protein 3D structures and for virtual screening. Adjustable parameters in two docking software were varied using DoE and parameter settings were identified which lead to improved results. In an additional study, we explored the nature of ligand-binding cavities in proteins since they are important factors in protein-ligand interactions, especially in the prediction of the function of newly found proteins. We developed a strategy, comprising a new set of descriptors and PCA, to map proteins based on their cavity physicochemical properties. Finally, we applied our developed strategies to design a set of glycopeptides which were used to study autoimmune arthritis. A combination of docking and statistical molecular design, synthesis and biological evaluation led to new binders for two different class II MHC proteins and recognition by a panel of T-cell hybridomas. New and interesting SAR conclusions could be drawn and the results will serve as a basis for selection of peptides to include in in vivo studies.

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  • 49.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Peptidomimetics derived from the bioactive hexapeptide angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) have been designed and synthesized. These peptidomimetics are aimed at inhibiting the insulin-regulated amino peptidase (IRAP), also known as the AT4 receptor. This membrane-bound zinc-metallopeptidase is currently under investigation regarding its potential as a target for cognitive enhancers. The work presented herein was based on stepwise replacement of the amino acid residues in Ang IV by natural and unnatural amino acids, non-peptidic building blocks, and also on the introduction of conformational constraints. Initially, we focused on the introduction of secondary structure mimetics and backbone mimetics. The C-terminal tripeptide His-Pro-Phe was successfully replaced by a γ-turn mimetic scaffold, 2-(aminomethyl)phenylacetic acid (AMPA), which was coupled via an amide bond to the carboxyl terminus of Val-Tyr-Ile. Substitution of Val-Tyr-Ile, Val-Tyr, Tyr-Ile and Tyr, respectively, by 4-hydroxydiphenylmethane scaffolds comprising a 1,3,5-substituted benzene ring as a central moiety unfortunately rendered peptidomimetics that were less potent than Ang IV. The subsequent approach involved the introduction of conformational constraints into Val-Tyr-Ile-AMPA by replacing Val and Ile by amino acid residues appropriate for disulfide cyclization or ring-closing metathesis. Chemically diverse structures encompassing an N-terminal 13- or 14-membered macrocyclic tripeptide and a C-terminal non-peptidic moiety were developed. Tyr2 and AMPA were modified to acquire further knowledge about the structure-activity relationships and, in addition, to improve the metabolic stability and reduce the polarity. Several of the compounds displayed a high capacity to inhibit IRAP and exhibited Ki values in the low nanomolar range. Hence, the new compounds were more than ten times more potent than the parent peptide Ang IV. Enhanced selectivity over the closely related aminopeptidase N (AP-N) was achieved, as well as improved stability against proteolysis by metallopeptidases present in the assays. However, additional investigations are required to elucidate the bioactive conformation(s) of the relatively flexible N-terminal macrocycles. The compounds presented in this thesis have provided important information on structure-activity relationships regarding the interaction of Ang IV-related pseudopeptides and peptidomimetics with IRAP. The best compounds in the series constitute important starting points for further discovery of Ang IV peptidomimetics suitable as tools in the investigation of IRAP and other potential targets for Ang IV. The literature presents strong support for the hypothesis that drug-like IRAP inhibitors would serve as a new type of future cognitive enhancers with potential use in the treatment of cognitive disorders, e.g. Alzheimer’s disease.

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  • 50.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Johnsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Erdélyi, Máté
    Department of Chemistry, University of Gothenburg.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 11, p. 3779-3792Article in journal (Refereed)
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

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