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  • 1.
    Arvidsson, Per
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Frackenpohl, J
    Seebach, D
    Syntheses an CD-Spectroscopic Investigations of Longer-Chain B-Peptides: Preparation by Solid-Phase Couplings of Single Amino Acids, Dipeptides, and Tripeptides2003In: Helvetica Chemica Acta, no 86, p. 1552-1553Article in journal (Refereed)
  • 2.
    Arvidsson, Per I.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska institutet.
    Domeij, Bengt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lind, Anna-Sara
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Ullerås, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Öppenheten förstör chansen till patent2015In: Svenska dagbladet, ISSN 2001-3868Article in journal (Other (popular science, discussion, etc.))
  • 3.
    Arvidsson, Per I.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Open for collaboration: an academic platform for drug discovery and development at SciLifeLab2016In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 21, no 10, p. 1690-1698Article, review/survey (Refereed)
    Abstract [en]

    The Science for Life Laboratory Drug Discovery and Development (SciLifeLab DDD) platform reaches out to Swedish academia with an industry-standard infrastructure for academic drug discovery, supported by earmarked funds from the Swedish government. In this review, we describe the build-up and operation of the platform, and reflect on our first two years of operation, with the ambition to share learnings and best practice with academic drug discovery centers globally. We also discuss how the Swedish Teacher Exemption Law, an internationally unique aspect of the innovation system, has shaped the operation. Furthermore, we address how this investment in infrastructure and expertise can be utilized to facilitate international collaboration between academia and industry in the best interest of those ultimately benefiting the most from translational pharmaceutical research - the patients.

  • 4.
    Arvidsson, Per
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Ryder, N
    Weiss, M
    Gross, G
    Kretz, O
    Woessner, R
    Seebach, D
    Antibiotic and Hemolytic Activity of a B2/B3 Peptide Capable of Folding into a 12/10-Helical Secondary Structure2003In: ChemBioChem, no 4, p. 1345-1347Article in journal (Refereed)
  • 5.
    Arvidsson, Per
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Organisk kemi.
    Ryder, Neil S.
    Weiss, H. Markus
    Hook, David F.
    Escalante, Jaime
    Seebach, Dieter
    Exploring the Antibacterial and Hemolytic Activity of Shorter- and Longer-Chain B-, a,B-, and y-Peptides, and of B-Peptides from B2-3-Aza- and B3-2-Methylidene-amino Acids Bearing Proteinogenic Side Chains - A Survey2005In: Chemistry & Biodiversity, Vol. 2, p. 401-420Article in journal (Refereed)
    Abstract [en]

    The antibacterial activities of 31 different b-, mixed a/B-, and y-peptides, as well as of B-peptides derived from B2-3-aza- and B3-2-methylidene-amino acids were assayed against six pathogens (Enterococcus faecails, STaphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa), and the results were compared with literature data. The interaction of these peptides with mammalian cells, as modeled by measuring the hemolysis of human erythrocytes, was also investigated. In addition to those peptides designed to fold into amphiphilic helical conformations with positive charges on one face of the helix, one new peptide with hemolytic activity was detected within the sample set. Moreover, it was demontrated that neither cationic peptides used for membrane translocation (B3-oligoarginines), nor mixeda/B- or y-peptides with somatostatin-mimicking activities display unwanted hemolytic activity.

  • 6. Borgegård, Tomas
    et al.
    Gustavsson, Susanne
    Nilsson, Charlotte
    Parpal, Santiago
    Klintenberg, Rebecka
    Berg, Anna-Lena
    Rosqvist, Susanne
    Serneels, Lutgarde
    Svensson, Samuel
    Olsson, Fredrik
    Jin, Shaobo
    Yan, Hongmei
    Wanngren, Johanna
    Jureus, Anders
    Ridderstad-Wollberg, Anna
    Wollberg, Patrik
    Stockling, Kenneth
    Karlström, Helena
    Malmberg, Asa
    Lund, Johan
    Arvidsson, Per I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    De Strooper, Bart
    Lendahl, Urban
    Lundkvist, Johan
    Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 48, p. 17297-17305Article in journal (Refereed)
    Abstract [en]

    γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.

  • 7.
    Borhade, Sanjay R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of Novel Aryl and Heteroaryl Acyl Sulfonimidamides via Pd-Catalyzed Carbonylation Using a Nongaseous Precursor2013In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 15, no 5, p. 1056-1059Article in journal (Refereed)
    Abstract [en]

    Hitherto unexplored aryl and heteroaryl acyl sulfonimidamides have been prepared through the development of a new Pd-catalyzed carbonylation protocol. This novel methodology, employing sulfonimidamides as nucleophiles and CO gas ex situ released from solid Mo(CO)(6) in a sealed two-chamber system, yields a wide range of carbamate protected acyl sulfonimidamides in good to excellent yields.

  • 8.
    Buttner, Frank
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. avd för organisk kemi.
    Norgren, Anna
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. avd för organisk kemi.
    Zhang, Suode
    Prabpai, Samran
    Kongsaeree, Palangpon
    Arvidsson, Per
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. avd för organisk kemi.
    Cyclic B-Tetra- and Pentapeptides: Synthesis through On-Resin Cyclization and Confomrational Studies by X-Ray, NMR and CD Spectroscopy and Theoretical Calculations2005In: Chem. Eur. J., Vol. 11, p. 6145-6158Article in journal (Refereed)
    Abstract [en]

    The solution-phase synthesis of the simplest cyclic B-tetrapeptide, cyclo(B-Ala)4 (4), as well as the solidphase syntheses through side chain anchoring and on-resin cyclization of the cyclic B3-tetrapeptide cyclo-(B3hPhe-B3hLeu-B3hLys-B3hGln-) (14) and the first cyclic B3-pentapeptide cyclo- (B3hVal-B3hPhe-B3Leu- B3hLys-B3hLys-) (19) are reported. Extensive computational as well as spectroscopic studies, including X-ray and NMR spectroscopy, were undertaken to determine the preferred conformations of these unnatural oligomers in solution and in the solid state. cyclo(B-Ala)4 (4) with no chiral side chains is shown to exist as a mixture of rapidly interchanging conformers in solution, whereas inclusion of chiral side chains in the cyclo-B3-tetrapetpride causes stabilizaton of one dominating conformer. The cyclic B3-pentapeptide on the other hand shows larger conformational freedom. The X-ray structure of achiral cyclo(B-Ala)4 (4) displays a Ci-symmetrical 16-membered ring with adjacent C=O and N-H atoms pointing pair wise up and down with respect to the ring plane. CD spectorscopic examinations of all cyclic B-peptides were undertaken and revealed results valuable as starting point for further structural investigations of these entities.

  • 9.
    Bylund, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Macsari, Istvan
    Besidski, Yevgeni
    Olofsson, Susanne
    Petersson, Carl
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bueters, Tjerk
    Novel bioactivation mechanism of reactive metabolite formation from phenyl methyl-isoxazoles2012In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 40, no 11, p. 2185-2191Article in journal (Refereed)
    Abstract [en]

    Recently, we described a series of phenyl methyl-isoxazole derivatives as novel, potent, and selective inhibitors of the voltage-gated sodium channel type 1.7 (Bioorg Med Chem Lett 21:3871-3876, 2011). The lead compound, 2-chloro-6-fluorobenzyl [3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbamate, showed unprecedented GSH and cysteine reactivity associated with NADPH-dependent metabolism in trapping studies using human liver microsomes. Additional trapping experiments with close analogs and mass spectra and NMR analyses suggested that the conjugates were attached directly to the 5′-methyl on the isoxazole moiety. We propose a mechanism of bioactivation via an initial oxidation of the 5′-methyl generating a stabilized enimine intermediate and a subsequent GSH attack on the 5′-methylene. Efforts to ameliorate reactive metabolite generation were undertaken to minimize the potential risk of toxicity. Formation of reactive metabolites could be significantly reduced or prevented by removing the 5′-methyl, by N-methylation of the carbamate; by replacing the nitrogen with a carbon or removing the nitrogen to obtain a carboxylate; or by inserting an isomeric 5′-methyl isoxazole. The effectiveness of these various chemical modifications in reducing GSH adduct formation is in line with the proposed mechanism. In conclusion, we have identified a novel mechanism of bioactivation of phenyl 5-methyl-isoxazol-4-yl-amines. The reactivity was attenuated by several modifications aimed to prevent the emergence of an enimine intermediate. Whether 5′-methyl isoxazoles should be considered a structural alert for potential formation of reactive metabolites is dependent on their context, i.e., 4′-nitrogen.

  • 10.
    Büttner, Frank
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Organisk kemi.
    Erdélyi, Máté
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Organisk kemi.
    Arvidsson, Per
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Organisk kemi.
    cyclo(ß-Asp-ß3-hVal-ß3-hLys)-Solid-Phase Synthesis and Solution Structure of a Water Soluble ß-Tripeptide2004In: Helvetica Chimica Acta, Vol. 87, p. 2735-2741Article in journal (Refereed)
  • 11. Chakka, Sai Kumar
    et al.
    Francis, Vivian
    Cele, Zamani E. D.
    Sosibo, Sphelele C.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kruger, Hendrik G.
    Maguire, Glenn E. M.
    Govender, Thavendran
    Asymmetric conjugate addition of thioglycolate to a range of chalcones using tetrahydroisoquinoline (TIQ) N,N '-dioxide ligands2012In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 23, no 8, p. 616-622Article in journal (Refereed)
    Abstract [en]

    A series of novel TIQ based N,N'-oxide ligands were synthesised and screened for their catalytic activity in the enantioselective conjugate addition of thioglycolate to chalcones. Bulky groups on the side chain of the TIQ backbone provided the highest enantioselectivity of up to 88% with 10 mol % catalyst loading. It was also observed that these reactions proceeded optimally in the presence of dichloromethane as a solvent. Screening of various metals emphasized La(OTf)(3) as the ideal pre-catalyst for this particular reaction.

  • 12.
    Hartikka, Antti
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Organisk kemi.
    Arvidsson, Per
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Rational design of asymmetric organocatalysts-increased reactivity and solvent scope with a tetrazolic acid2004In: Tetrahedron Asymmetry, Vol. 15, p. 1831-1834Article in journal (Refereed)
    Abstract [en]

    Replacement of the carboxylic acid functionality in the widely used organocatalyst proline with a tetrazolic acid leads to a catalyst with increased reactivity and solvent scope, as demonstrated in the direct catalytic asymmetric aldol reaction.

  • 13.
    Hartikka, Antti
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Arvidsson, Per. I
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Tetrazolic Acid Functionalized Dihydroindol: Rational Design of a Highly Selective Cyclopropanation Organocatalyst2007In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 15, p. 5874-5877Article in journal (Refereed)
    Abstract [en]

    Herein we wish to report our development of an improved catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enantioselective organocatalyzed cyclopropanation of α,β-unsaturated aldehydes with sulfur ylides. The new organocatalyst readily facilitates the enantioselective organocatalytic cyclopropanation, providing cyclized product in excellent diastereoselectivities ranging from 96% to 98% along with enantioselectivities exceeding 99% enantiomeric excess for all reacted α,β-unsaturated aldehydes. The new catalyst provides the best results so far reported for intermolecular enantioselective organocatalyzed cyclopropanation.

  • 14.
    Hartikka, Antti
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Slosarczyk, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Arvidsson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Application of novel sulfonamides in enantioselective organocatalyzed cyclopropanation2007In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 18, no 12, p. 1403-1409Article in journal (Refereed)
    Abstract [en]

    Three novel aryl sulfonamides derived from (2S)-indoline-2-carboxylic acid have been obtained and used as organocatalysts. The catalysts incorporate diverse functionality on the phenyl ring, enabling steric, and electronic fine tuning of the catalysts. The catalysts facilitate the reaction between a range of α,β-unsaturated aldehydes and sulfur ylides, thus providing cyclopropane products in enantiomeric excesses of up to 99%.

  • 15.
    Hedberg, Christian
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Källström, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Arvidsson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Brandt, Peter
    Andersson, Pher
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Mechanistic Insights into the Phosphine-Free RuCp*-Diamine-Catalyzed Hydrogenation of Aryl Ketones: Experimental and Theoretical Evidence for an Alcohol-Mediated Dihydrogen Activation2005In: J. Am. Chem. Soc., no 127, p. 15083-15090Article in journal (Refereed)
    Abstract
  • 16. Hemmaragala, Nanjundaswamy M.
    et al.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Maguire, Glenn E. M.
    Kruger, Hendrik G.
    Govender, Thavendran
    Interaction of beta-Amyloid Interactions with Peptide Functionalized Gold Nanoparticles2012In: Journal of Nanoscience and Nanotechnology, ISSN 1533-4880, E-ISSN 1533-4899, Vol. 12, no 3, p. 2179-2184Article in journal (Refereed)
    Abstract [en]

    The physicochemical properties of gold nanoparticles (GNPs) functionalized with peptides and N-methylated peptides were studied with respect to their interaction with beta-amyloid (1-42). Peptides with sequences of CGGIGLMVG and CGGGGGIGLMVG linked with GNPs of an average diameter of 13 nm were employed for this study. The peptide-GNPs were found to be soluble and dispersed at pH 7.4 in a sodium phosphate aqueous buffer solution. The resonance spectra of each peptide coated GNP was measured in the absence and presence of beta-amyloid (1-42). The difference in the intensity of the lambda(max) of the resonance absorption bands was attributed to the interaction of the functionalized GNPs with the protein. Particles bearing the CGGGGGIGLMVG sequence exhibited the largest change in lambda(max) intensity; the prevention of fibril formation and inhibition of cytotoxicity was also examined.

  • 17. Honarparvar, Bahareh
    et al.
    Makatini, Maya M.
    Pawar, Sachin A.
    Petzold, Katja
    Soliman, Mahmoud E. S.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sayed, Yasien
    Govender, Thavendran
    Maguire, Glenn E. M.
    Kruger, Hendrik G.
    Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies2012In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 7, no 6, p. 1009-1019Article in journal (Refereed)
    Abstract [en]

    Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC50 values in the 0.50.6 mu M range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space 1H,1H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.

  • 18. Macsari, Istvan
    et al.
    Besidski, Yeygeni
    Csjernyik, Gabor
    Nilsson, Linda I.
    Sandberg, Lars
    Yngve, Ulrika
    Ahlin, Kristofer
    Bueters, Tjerk
    Eriksson, Anders B.
    Lund, Per-Eric
    Venyike, Elisabet
    Oerther, Sandra
    Blakeman, Karin Hygge
    Luo, Lei
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 15, p. 6866-6880Article in journal (Refereed)
    Abstract [en]

    The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

  • 19. Makatini, Maya M.
    et al.
    Petzold, Katja
    Alves, Claudio Nahum
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Honarparvar, Bahareh
    Govender, Patrick
    Govender, Thavendran
    Kruger, Hendrik G.
    Sayed, Yasien
    Lameira, Jeronimo
    Maguire, Glenn E. M.
    Soliman, Mahmoud E. S.
    Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors2013In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 28, no 1, p. 78-88Article in journal (Refereed)
    Abstract [en]

    In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC50 values ranging from 0.5 up to 0.75 mu M against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC50 (0.5 mu M), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC50 values (0.5-10 mu M). The PCU-peptides and peptoides were several orders less toxic (145 mu M for 11 and 102 mu M for 11 peptoid) to human MT-4 cells than lopinavir (0.025 mu M). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases.

  • 20. Makatini, Maya M.
    et al.
    Petzold, Katja
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Honarparvar, Bahareh
    Govender, Thavendran
    Maguire, Glenn E. M.
    Parboosing, Raveen
    Sayed, Yasien
    Soliman, Mahmoud E. S.
    Kruger, Hendrik G.
    Synthesis, screening and computational investigation of pentacycloundecane-peptoids as potent CSA-HIV PR inhibitors2012In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 57, p. 459-467Article in journal (Refereed)
    Abstract [en]

    Herein, we present the first pentacycloundecane (PCU) diol peptoid derived HIV protease inhibitors with IC50 values ranging from 6.5 to 0.075 mu M. Five derivatives were synthesized in an attempt to understand the structure activity relationship of this class of compounds for HIV protease inhibition. NMR spectroscopy (new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy, EASY-ROESY) was employed to determine the predominant conformation of the active compound. In this study docking studies and MD simulations provided insight into the binding theme of this class of peptoid inhibitors to the CSA-HIV PR active site. Conserved and stable hydrogen bonding between the hydroxyl groups of the inhibitors and the active site Asp25/Asp25' residues were observed from the docking and along the MD trajectories.

  • 21. Makatini, Maya M.
    et al.
    Petzold, Katja
    Sriharsha, Shimoga N.
    Ndlovu, N.
    Soliman, Mahmoud E. S.
    Honarparvar, Bahareh
    Parboosing, Raveen
    Naidoo, Anneta
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sayed, Yasien
    Govender, Patrick
    Maguire, Glenn E. M.
    Kruger, Hendrik G.
    Govender, Thavendran
    Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: A hybrid 2D NMR and docking/QM/MM/MD approach2011In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, no 9, p. 3976-3985Article in journal (Refereed)
    Abstract [en]

    Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC(50) activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25', was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.

  • 22. Maldonado, Matias Funes
    et al.
    Sehgelmeble, Fernando
    Bjarnemark, Fanny
    Svensson, Mats
    Ahman, Jens
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis and arylation of unprotected sulfonimidamides2012In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, no 36, p. 7456-7462Article in journal (Refereed)
    Abstract [en]

    Herein we evaluate different methodologies for the synthesis of unprotected sulfonimidamides. Three different procedures that allow orthogonal deprotection of the imine nitrogen under acidic, nucleophilic, and basic conditions were established. Moreover, we present a highly efficient methodology for functionalization of the imine nitrogen through Pd-catalyzed C-N arylation. RuPhos ligand was shown to allow short reaction time, excellent yields, and allowed coupling of both aryl halides and heteroaryl bromides.

  • 23. Naicker, Tricia
    et al.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kruger, Hendrik G.
    Maguire, Glenn E. M.
    Govender, Thavendran
    Microwave-Assisted Synthesis of Guanidine Organocatalysts Bearing a Tetrahydroisoquinoline Framework and Their Evaluation in Michael Addition Reactions2012In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 17, p. 3331-3337Article in journal (Refereed)
    Abstract [en]

    The simple and practical syntheses of chiral guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction of malonates and beta-keto esters with nitro-olefins is reported. These organocatalysts are the first of their kind based on a tetrahydroisoquinoline framework. In addition, a microwave-assisted procedure for introducing the guanidine unit onto amino amide derivatives is reported. The chiral products were obtained with quantitative chemical efficiency (up to 99 % yield) and excellent enantioselectivity (up to 97 % ee).

  • 24. Naicker, Tricia
    et al.
    Arvidsson, Per I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kruger, Hendrik G
    Maguire, Glenn E M
    Govender, Thavendran
    Tetrahydroisoquinoline-Based N-Oxides as Chiral Organocatalysts for the Asymmetric Allylation of Aldehydes2011In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2011, no 34, p. 6923-6932Article in journal (Refereed)
    Abstract [en]

    The short synthesis of a series of novel chiral N-oxideorganocatalysts and their evaluation in the asymmetric allylation reaction of aromatic and α-β-unsaturated aldehydes with allyltrichlorosilane is reported. These readily modifiable organocatalysts are the first of their kind based on the tetrahydroisoquinoline framework. The chiral homoallyl products were obtained with good chemical efficiency (up to 93 % yield) and high enantioselectivity (up to 91 % ee) under mild reaction conditions (23 °C).

  • 25.
    Norgren, Anna S.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Geitmann, Matthis
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Biomolecular Recognition of Glycosylated β3-Peptides by GalNAc Specific Lectins2007In: Journal of Molecular Recognition, ISSN 0952-3499, E-ISSN 1099-1352, Vol. 20, no 2, p. 132-138Article in journal (Refereed)
    Abstract [en]

    The molecular recognition of a novel kind of hybrid conjugates, composed of artificial biomimetic β-peptide oligomers with an O-linked natural N-acetyl-galactosamine (the Tn-antigen) residue, by four different GalNAc specific lectins was investigated using surface plasmon biosensor technology. The influence of the peptide and the glycosyl moiety on the recognition was studied using two glycosylated β3-heptapeptides, a glycosylated α-heptapeptide, two β-amino acid containing dipeptides, and monomeric αGalNAc-O-Thr. Although all four lectins displayed a decreased affinity for the carbohydrate residue when attached to a peptide, as compared to the monomeric Tn-antigen, the peptide part was found to have distinct effects on the binding kinetics - indicating that varying degrees of protein-peptide interactions occurred in the recognition process. Likewise, the lectins did not discriminate between β3-peptides and the α-peptide, but the β- linkage of the galactose had a detrimental effect for at least two of the lectins.

  • 26.
    Norgren, Anna S.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Norberg, Thomas
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Glycosylated Foldamers: Synthesis of Carbohydrate-modified β3hSer and Incorporation into β-Peptides2007In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 11, p. 717-727Article in journal (Refereed)
    Abstract [en]

    Fmoc-protected β3hserine (β3hSer) was prepared and O-linked to suitably protected N-acetylgalactosamine (GalNAc) and N-acetylglucosamine (GlcNAc) derivatives. Glycosylation of β3hSer was made by two independent routes: either by direct glycosyl linkage to the β3hSer, or linkage to natural L-Ser and then utilizing the carbohydrate moiety as a protecting group in an Arndt–Eistert homologation. Both procedures gave the novel glycosylated β3-amino acids Fmoc-β3hSer(α-D-GalNAc(Ac)3)-OH (1a), its β-anomer (1b), and Fmoc-β3hSer(β-D-GlcNAc(Ac)3)-OH (2), which were utilized in the solid-phase peptide synthesis of four glycosylated dipeptides (3a–d) and two heptapeptides (4a–b). The preparation of β-amino acids bearing common post-translational modifiers represents an important step towards functionalized foldamers with broad applications in biomedical research.

  • 27.
    Norgren, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Zhang, Suode
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Arvidsson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Synthesis and circular dichroism spectroscopic investigations of oligomeric β-peptoids with α-chiral side chains2006In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 8, no 20, p. 4533-4536Article in journal (Refereed)
    Abstract [en]

    Biomimetic oligomers are of large interest both as targets for combinatorial and parallel synthetic efforts and as foldamers. For example, shorter peptoid derivatives of beta-peptides, i.e., oligo-N-substituted beta-Ala, have been described as potential lead structures. Herein, we describe a solid-phase synthetic route to beta-peptoids with alpha-chiral aromatic N-substituents up to 11 residues long. Furthermore, the folding propensities of these oligomers were investigated by circular dichroism (CD) spectroscopy.

  • 28.
    Sawant, Rajiv T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Stevenson, Joanne
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Organocatalytic asymmetric cross-aldol reaction of 2-chloroethoxy acetaldehyde: diversity-oriented synthesis of chiral substituted 1,4-dioxanes and morpholines2013In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 24, no 2-3, p. 134-141Article in journal (Refereed)
    Abstract [en]

    Herein we report a facile organocatalytic asymmetric direct cross-aldol reaction of 2-chloroethoxy acetaldehyde with aromatic aldehydes using (S)-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol as an organocatalyst to afford anti-2-(2-chloroethoxy)-1-arylpropane-1,3-diols with excellent enantioselectivities (95-98%) and moderate diastereoselectivities (3.5-7:1). The 1,3-diols, obtained after the aldehyde reduction, represent highly functional intermediates that allow for further diversification into both chiral 1,4-dioxanes and morpholines, compounds that frequently display interesting biological activities.

  • 29. Sehgelmeble, Fernando
    et al.
    Jansson, Juliette
    Ray, Colin
    Rosqvist, Susanne
    Gustavsson, Susanne
    Nilsson, Linda I
    Minidis, Alexander
    Holenz, Jörg
    Rotticci, Didier
    Lundkvist, Johan
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sulfonimidamides as Sulfonamides Bioisosteres: Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ-Secretase Inhibitors2012In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 7, no 3, p. 396-399Article in journal (Refereed)
    Abstract [en]

    The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.

  • 30. Yngve, Ulrika
    et al.
    Paulsen, Kim
    Macsari, Istvan
    Sundstrom, Marie
    Santangelo, Ellen
    Linde, Christian
    Bogar, Krisztian
    Lake, Fredrik
    Besidski, Yevgeni
    Malmborg, Jonas
    Stromberg, Kia
    Appelkvist, Paulina
    Radesater, Ann-Cathrine
    Olsson, Fredrik
    Bergstrom, Daniel
    Klintenberg, Rebecka
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Triazolopyrimidinones as gamma-secretase modulators: structure-activity relationship, modulator profile, and in vivo profiling2013In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 4, no 2, p. 422-431Article in journal (Refereed)
    Abstract [en]

    The structure-activity relationship for a series of potent g-secretase modulators based on the 6,7-dihydro4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one scaffold is described. Furthermore, we report details regarding the modulator profile on A beta processing, as well as in vivo efficacy, for the optimized compounds.

  • 31. Yngve, Ulrika
    et al.
    Söderman, Peter
    Svensson, Mats
    Rosqvist, Susanne
    Arvidsson, Per I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Imidazopyridine-based inhibitors of glycogen synthase kinase 3: synthesis and evaluation of amide isostere replacements of the carboxamide scaffold2012In: Chemistry and Biodiversity, ISSN 1612-1872, E-ISSN 1612-1880, Vol. 9, no 11, p. 2442-2452Article in journal (Refereed)
    Abstract [en]

    In this study, we explored the effect of bioisostere replacement in a series of glycogen synthase kinase 3 (GSK3) inhibitors based on the imidazopyridine core. The synthesis and biological evaluation of a number of novel sulfonamide, 1,2,4-oxadiazole, and thiazole derivates as amide bioisosteres, as well as a computational rationalization of the obtained results are reported.

  • 32.
    Zhang, Suode
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Avd för organisk kemi.
    Govender, Thavendran
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Avd för organisk kemi.
    Norström, Thomas
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Avd för organisk kemi.
    Arvidsson, Per
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Avd för organisk kemi.
    An Improved Synthesis of Fmoc-N-methyl-a-amino Acids2005In: J. Org. Chem., no 70, p. 6918-6920Article in journal (Refereed)
1 - 32 of 32
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