Strukturbasiertes Design, Synthese und Affinitätsbestimmung neuartiger HIV-1-Protease-Inhibitoren

Mit dem humanen Immunschwäche Virus (HIV), dem Verursacher des erworbenen Immunschwäche Syndroms, welches auch als AIDS (Acquired Immunodeficiency Syndrom) bezeichnet wird, sind heute weltweit 34 Millionen Menschen infiziert. Trotz beachtlicher Erfolge mit den 26 aktuell zugelassenen Wirkstoffen im...

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Gespeichert in:
1. Verfasser: Klee, Nina
Beteiligte: Diederich, Wibke (Prof. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2013
Pharmazeutische Chemie
Ausgabe:http://dx.doi.org/10.17192/z2013.0394
Schlagworte:
HIV
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1. Broder, S., The development of antiretroviral therapy and its impact on the HIV- 1/AIDS pandemic. Antiviral Research, 2010. 85(1): p. 1-18. 17. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2012. Available from: http://aidsinfo.nih.gov/guidlines 18. WHO. Antiretroviral Therapy. Available from: http://www.who.int/topics/antiretroviral_therapy/en/. 19. Mehellou, Y. and E. De Clercq, Twenty-Six Years of Anti-HIV Drug Discovery: Where Do We Stand and Where Do We Go? Journal of Medicinal Chemistry, 2009. 53(2): p. 521-538. 20. Arzneimittelinformationen für Ärzte und Apotheker. Available from: www.fachinfo.de. 21. Sun, L.-Q., et al., Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorganic & Medicinal Chemistry Letters, 2012. 22(7): p. 2376-2379.


2. http://archiv.ub.uni-marburg.de/diss/z2012/0082


3. Jones, G., et al., Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology, 1997. 267(3): p. 727-748.


4. Richter, M., et al., P-Glycoprotein Effects of Cyclic Urea HIV Protease Inhibitor DMP 323 in Competitional Absorption Studies. Archiv der Pharmazie, 2006. 339(11): p. 625-628.


5. Dunitz, J.D. and R. Taylor, Organic Fluorine Hardly Ever Accepts Hydrogen Bonds. Chemistry – A European Journal, 1997. 3(1): p. 89-98.


6. Kim, A. and J.H. Hong, Synthesis and Antiviral Evaluation of Novel Exomethylene Acyclic Nucleosides and Phosphonic Acid Nucleosides. Archiv der Pharmazie, 2005. 338(11): p. 528-533.


7. Faler, C.A. and M.M. Joullié, The Kulinkovich Reaction in the Synthesis of Constrained N,N-Dialkyl Neurotransmitter Analogues. Organic Letters, 2007. 9(10): p. 1987-1990. 326 promising new scaffold for HIV Protease Inhibitors. (Poster, ausgezeichnet mit einem Posterpreis)


8. Böttcher, J., et al., Targeting the Open-Flap Conformation of HIV-1 Protease with Pyrrolidine-Based Inhibitors. ChemMedChem, 2008. 3(9): p. 1337-1344.


9. Rajapakse, H.A., et al., Strategies towards Improving the Pharmacokinetic Profile of ε-Substituted Lysinol-Derived HIV Protease Inhibitors. ChemMedChem, 2011. 6(2): p. 253-257.


10. Castro, H.C., et al., Looking at the proteases from a simple perspective. Journal of Molecular Recognition, 2011. 24(2): p. 165-181.


11. Dandache, S., et al., PL-100, a novel HIV-1 protease inhibitor displaying a high genetic barrier to resistance: An in vitro selection study. Journal of Medical Virology, 2008. 80(12): p. 2053-2063.


12. Rockstroh, J.K., Epidemiologie und Transmission der HIV-Infektion. Pharmazie in unserer Zeit, 1999. 28(2): p. 95-101.


13. Murphy, M.D., G.I. Marousek, and S. Chou, HIV protease mutations associated with amprenavir resistance during salvage therapy: importance of I54M. Journal of Clinical Virology, 2004. 30(1): p. 62-67.


14. Böttcher, J., et al., Structural and Kinetic Analysis of Pyrrolidine-Based Inhibitors of the Drug-Resistant Ile84Val Mutant of HIV-1 Protease. Journal of Molecular Biology, 2008. 383(2): p. 347-357.


15. Blum, A., et al., Two Solutions for the Same Problem: Multiple Binding Modes of Pyrrolidine-Based HIV-1 Protease Inhibitors. Journal of Molecular Biology, 2011. 410(4): p. 745-755.


16. Du, Z., et al., pKa Coupling at the Intein Active Site: Implications for the Coordination Mechanism of Protein Splicing with a Conserved Aspartate. Journal of the American Chemical Society, 2011. 133(26): p. 10275-10282.


17. Vargas, R., et al., How Strong Is the Cα−H···OC Hydrogen Bond? Journal of the American Chemical Society, 2000. 122(19): p. 4750-4755.


18. Weiss, R.A., Gulliver's travels in HIVland. Nature, 2001. 410(6831): p. 963-967.


19. Davies, S.G., et al., Asymmetric synthesis of 3,4-anti-and 3,4-syn-substituted aminopyrrolidines via lithium amide conjugate addition. Organic & Biomolecular Chemistry, 2007. 5(12): p. 1961-1969.


20. Dell'Amico, D.B., F. Calderazzo, and U. Giurlani, Metal-assisted electrophilic reactions on carbon dioxide: synthesis of mixed carboxylato-carbamato anhydrides. Journal of the Chemical Society, Chemical Communications, 1986(13): p. 1000-1001.


21. Ala, P.J., et al., Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors. Journal of Biological Chemistry, 1998. 273(20): p. 12325-12331.


22. Perryman, A.L., et al., Fragment-Based Screen against HIV Protease. Chemical Biology & Drug Design, 2010. 75(3): p. 257-268.


23. Callebaut, C., et al., In Vitro Characterization of GS-8374, a Novel Phosphonate- Containing Inhibitor of HIV-1 Protease with a Favorable Resistance Profile. Antimicrobial Agents and Chemotherapy, 2011. 55(4): p. 1366-1376.


24. Hightower, M. and E.G. Kallas, Diagnosis, antiretroviral therapy, and emergence of resistance to antiretroviral agents in HIV-2 infection: a review. Brazilian Journal of Infectious Diseases, 2003. 7: p. 07-15.


25. Jacobsen, E.J., et al., 3-Phenyl-Substituted Imidazo[1,5-a]quinoxalin-4-ones and Imidazo[1,5-a]quinoxaline Ureas That Have High Affinity at the GABAA/Benzodiazepine Receptor Complex. Journal of Medicinal Chemistry, 1996. 39(19): p. 3820-3836.


26. 50 g (1.31 mmol) tert-Butyl-(3S,4S)-3,4-bis(benzylamino)pyrrolidin-1-carboxylat 140


27. Oxalylchlorid (alle 30 min 27.5 µl) zugegeben und weitere 30 min gerührt. Nach Entfernen des Lösungsmittels am Rotavapor und Aufreinigung mittels MPLC (DCM/EtOAc 30:70) wurden 112 mg (20 %) von 145 in Form eines farblosen Feststoffs erhalten.


28. Simona Koščová, M.B., Jana Hodačová, A Facile Synthesis of Selectively Protected Linear Oligoamines. Collect. Czech. Chem. Commun. , 2003. 68: p. 7. 78. Specker, E., et al., Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases: Design, Synthesis, and Structural Characterization. Journal of Medicinal Chemistry, 2005. 48(21): p. 6607-6619.


29. Demko, Z.P. and K.B. Sharpless, An Intramolecular [2 + 3] Cycloaddition Route to Fused 5-Heterosubstituted Tetrazoles. Organic Letters, 2001. 3(25): p. 4091- 4094.


30. Toth, M.V. and G.R. Marshall, A simple, continuous fluorometric assay for HIV protease. International Journal of Peptide and Protein Research, 1990. 36(6): p. 544-550.


31. Ausbeute: 112 mg (20 %) (weißer Feststoff)


32. The Public Health Agency of Canada, HIV/AIDS Epi Updates -July 2010. Available from: http://www.phac-aspc.gc.ca/aids-sida/publication/epi/2010/12- eng.php. 32. HIV&Virology News 2. 2012; Available from: www.hivvirology.com.


33. Neue antiretrovirale Substanzen. Available from: www.hivinfo.de.


34. UNAIDS REPORT ON THE GLOBAL AIDS EPIDEMIC 2010. Available from: www.unaids.org 4. World AIDS Day Report. 2011. Available from: www.unaids.org 5. GLOBAL HIV/AIDS RESPONSE – Epidemic update and health sector progress towards Universal Access – Progress Report. 2011. Available from: www.unaids.org 6.


35. Kovalevsky, A.Y., et al., Caught in the Act: The 1.5 Å Resolution Crystal Structures of the HIV-1 Protease and the I54V Mutant Reveal a Tetrahedral Reaction Intermediate. Biochemistry, 2007. 46(51): p. 14854-14864. 28. DEBOUCK, C., The HIV-1 Protease as a Therapeutic Target for AIDS. AIDS Research and Human Retroviruses, 1992. 8(2).


36. Esté, J.A. and T. Cihlar, Current status and challenges of antiretroviral research and therapy. Antiviral Research, 2010. 85(1): p. 25-33.


37. Klebe, G., Wirkstoffdesign 2009: Spektrum. 57. Bagossi, P., et al., Development of a microtiter plate fluorescent assay for inhibition studies on the HTLV-1 and HIV-1 proteinases. Journal of Virological Methods, 2004. 119(2): p. 87-93.


38. Chau, C.-M. and K.-M. Liu, Diels-Alder reactions of three fused nitrogen- containing bicyclic enones: an efficient method toward novel nitrogen-containing 9 LITERATURVERZEICHNIS 319 angular tricyclic skeletons. Organic & Biomolecular Chemistry, 2008. 6(17): p. 3127-3134.


39. D'Aquila, R.T.S., J. M.; Brun-Vézinet, F.; Clotet, B.; Conway, B.; Demeter, L. M.; Grant, R. M.; Johnson, V. A.; Kuritzkes, D. R.; Loveday, C.; Shafer, R. W.; Richman, D. D., Drug Resistance Mutations in HIV-1. Top. HIV Med, 2002. 10(5): p. 21-25.


40. Williams, D.B.G. and M. Lawton, Drying of Organic Solvents: Quantitative Evaluation of the Efficiency of Several Desiccants. The Journal of Organic Chemistry, 2010. 75(24): p. 8351-8354.


41. Neudert, G. and G. Klebe, DSX: A Knowledge-Based Scoring Function for the Assessment of Protein–Ligand Complexes. Journal of Chemical Information and Modeling, 2011. 51(10): p. 2731-2745.


42. Liu, F., et al., Effect of Flap Mutations on Structure of HIV-1 Protease and Inhibition by Saquinavir and Darunavir. Journal of Molecular Biology, 2008. 381(1): p. 102-115.


43. Kramer, B., M. Rarey, and T. Lengauer, Evaluation of the FLEXX incremental construction algorithm for protein–ligand docking. Proteins: Structure, Function, and Bioinformatics, 1999. 37(2): p. 228-241.


44. Neudert, G. and G. Klebe, fconv: format conversion, manipulation and feature computation of molecular data. Bioinformatics, 2011. 27(7): p. 1021-1022. 320


45. Hilderbrand, S.A., M.H. Lim, and S.J. Lippard, Fluorescence-based Nitric Oxide Detection Topics in Fluorescence Spectroscopy, C.D. Geddes and J.R. Lakowicz, Editors. 2005, Springer US. p. 163-188.


46. Scott, D.E., et al., Fragment-Based Approaches in Drug Discovery and Chemical Biology. Biochemistry, 2012. 51(25): p. 4990-5003.


47. Pantoliano, M.W., et al., High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery. Journal of Biomolecular Screening, 2001. 6(6): p. 429-440.


48. Ho, D.D. and P.D. Bieniasz, HIV-1 at 25. Cell, 2008. 133(4): p. 561-565.


49. HIV-1 Protease A Target for AIDS Therapy. 2000. Available from: www.pdb.org 317


50. Fanales-Belasio, E., et al., HIV virology and pathogenetic mechanisms of infection: a brief overview. Annali dell'Istituto Superiore di Sanità, 2010. 46: p. 5- 14.


51. John, V., et al., Human β-Secretase (BACE) and BACE Inhibitors. Journal of Medicinal Chemistry, 2003. 46(22): p. 4625-4630.


52. Virgin, H.W. and B.D. Walker, Immunology and the elusive AIDS vaccine. Nature, 2010. 464(7286): p. 224-231.


53. Hopkins, A.L., C.R. Groom, and A. Alex, Ligand efficiency: a useful metric for lead selection. Drug Discovery Today, 2004. 9(10): p. 430-431.


54. GDCh Fachgruppentagung "Frontiers in Medicinal Chemistry", Universität Münster N. Klee, K. Linde, I. Lindemann, G. Klebe, W. E. Diederich, New Inhibitors for an Old Target: Piperidines and Pyrrolidines to Block HIV Protease. (Poster) Nov. 2009 Doktorandenforum der Studienstiftung des deutschen Volkes, Koppelsberg Vortrag " Wege zu neu neuartigen HIV-Protease Inhibitoren " Okt. 2009 2. Internationales Symposium " Novel Agents against Infectious Diseases – An Interdisciplinary Approach " , Universität Würzburg Publikationen N. Klee, P. E. Wong, B. Baragana, F. El Mazouni, M. A. Phillips, M. P. Barrett, I. H. Gilbert Selective delivery of 2-hydroxy APA to Trypanosoma brucei using the melamine motif.


55. Bermejo, M., et al., PAMPA—a drug absorption in vitro model: 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones. European Journal of Pharmaceutical Sciences, 2004. 21(4): p. 429-441.


56. Kell, D.B., P.D. Dobson, and S.G. Oliver, Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only. Drug Discovery Today, 2011. 16(15–16): p. 704-714.


57. Lalezari, J.P., et al., Preliminary safety and efficacy data of brecanavir, a novel HIV-1 protease inhibitor: 24 week data from study HPR10006. Journal of Antimicrobial Chemotherapy, 2007. 60(1): p. 170-174.


58. Protein Data Bank. Available from: www.pdb.org.


59. Lam, P., et al., Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science, 1994. 263(5145): p. 380-384.


60. Klebe, G., Recent developments in structure-based drug design. Journal of Molecular Medicine, 2000. 78(5): p. 269-281.


61. Yung-Chi, C. and W.H. Prusoff, Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochemical Pharmacology, 1973. 22(23): p. 3099-3108.


62. Protease Inhibitor, Shows In Vitro an Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors. Antimicrobial Agents and Chemotherapy, 2011. 55(12): p. 5723-5731.


63. Gololobov, Y.G., I.N. Zhmurova, and L.F. Kasukhin, Sixty years of staudinger reaction. Tetrahedron, 1981. 37(3): p. 437-472.


64. Blum, A., et al., Structure-Guided Design of C2-Symmetric HIV-1 Protease Inhibitors Based on a Pyrrolidine Scaffold. Journal of Medicinal Chemistry, 2008. 51(7): p. 2078-2087.


65. Blum, A., Strukturbasiertes Design und Synthese von Pyrrolidinen als Inhibitoren der HIV-1-Protease. Dissertation, Philipps-Universität Marburg, 2007.


66. Lindemann, I., Strukturbasiertes Wirkstoffdesign am Beispiel der Zielproteine HIV-1 Protease, Transglutaminase 2 und Faktor XIII. Dissertation, Philipps- Universität Marburg, 2011.


67. Vieira, E., et al., Substituted piperidines -highly potent renin inhibitors due to induced fit adaptation of the active site. Bioorganic & Medicinal Chemistry Letters, 1999. 9(10): p. 1397-1402.


68. tert-Butyl-(4aS,7aS)-1,4-dibenzyl-2,3-dioxo-4a,5,7,7a-tetrahydropyrrolo[3,4- b]pyrazin-6-carboxylat (145)


69. Mager, P.P., The active site of HIV-1 protease. Medicinal Research Reviews, 2001. 21(4): p. 348-353.


70. Maksimovic-Ivanic, D., et al., The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt. Molecular Cancer Therapeutics, 2009. 8(5): p. 1169-1178. 318


71. Lineweaver, H. and D. Burk, The Determination of Enzyme Dissociation Constants. Journal of the American Chemical Society, 1934. 56(3): p. 658-666. 106. Buchwald, S.L. and R.B. Nielsen, Kinetics and substituent effects in the formation of zirconocene thioaldehyde complexes: .beta.-hydride elimination versus cyclometalation. Journal of the American Chemical Society, 1988. 110(10): p. 3171-3175.


72. Specker, E., et al., Unexpected Novel Binding Mode of Pyrrolidine-Based Aspartyl Protease Inhibitors: Design, Synthesis and Crystal Structure in Complex with HIV Protease. ChemMedChem, 2006. 1(1): p. 106-117.


73. Koike, R., et al., Unprecedented chemiluminescence behaviour during peroxyoxalate chemiluminescence of oxalates with fluorescent or electron- donating aryloxy groups. Luminescence, 2006. 21(3): p. 164-173. 84. lzdebski, J. and D. Pawlak, A New Convenient Method for the Synthesis of Symmetrical and Unsymmetrical N,N′-Disubstituted Ureas. Synthesis, 1989. 1989(06): p. 423-425.


74. wurden in 40 ml DCM gelöst und mit 0.91 ml DIPEA (5.24 mmol) versetzt. Die Reaktionsmischung wurde auf -50 °C gekühlt, innerhalb von 2 h 110 µl (1.31 mmol)


75. Bräse, S., et al., Organic Azides: An Exploding Diversity of a Unique Class of Compounds. Angewandte Chemie International Edition, 2005. 44(33): p. 5188- 5240.


76. Specker, E., et al., An Old Target Revisited: Two New Privileged Skeletons and an Unexpected Binding Mode For HIV-Protease Inhibitors. Angewandte Chemie International Edition, 2005. 44(20): p. 3140-3144.


77. Spitzmüller, A., H.F.G. elec, and G. Klebe, MiniMuDS: A New Optimizer using Knowledge-Based Potentials Improves Scoring of Docking Solutions. Journal of Chemical Information and Modeling, 2011. 51(6): p. 1423-1430.


78. Swamy, K.C.K., et al., Mitsunobu and Related Reactions: Advances and Applications. Chemical Reviews, 2009. 109(6): p. 2551-2651.


79. Varala, R., S. Nuvula, and S.R. Adapa, Molecular Iodine-Catalyzed Facile Procedure for N-Boc Protection of Amines. The Journal of Organic Chemistry, 2006. 71(21): p. 8283-8286.


80. Bernard Loev, J.H.M., Richard E. Brown, Howard Jones, Robert Kahen, Fu-Chih Huang, and P.S.-G. Atul Khandwala, and Mitchell J. Leibowitd, 1,2,4-Triazolo[ 4,3-a ]quinoxaline-l,4-diones as Antiallergic Agents. J. Med. Chem., 1985. 28: p. 4. 87. Group, C.C. Molecular Operating Environment. Available from: http://www.chemcomp.com/software.htm.


81. U.S. Food and Drug Administration. Available from: http://www.fda.gov/.


82. Canducci, F., et al., The new and less toxic protease inhibitor saquinavir–NO maintains anti-HIV-1 properties in vitro indistinguishable from those of the parental compound saquinavir. Antiviral Research, 2011. 91(3): p. 292-295. 44. GlaxoSmithKline. Available from: http://www.gsk.com/ 45. Concert Pharmaceuticals, Inc. Available from: http://www.concertpharma.com/ 46. Dierynck, I., et al., TMC310911, a Novel Human Immunodeficiency Virus Type 1


83. Köster, H., et al., A Small Nonrule of 3 Compatible Fragment Library Provides High Hit Rate of Endothiapepsin Crystal Structures with Various Fragment Chemotypes. Journal of Medicinal Chemistry, 2011. 54(22): p. 7784-7796. 98. GRID. Available from: http://www.moldiscovery.com/soft_grid.php. 99. Thaisrivongs, S., et al., Structure-Based Design of Novel HIV Protease Inhibitors: Carboxamide-Containing 4-Hydroxycoumarins and 4-Hydroxy-2-pyrones as Potent Nonpeptidic Inhibitors. Journal of Medicinal Chemistry, 1995. 38(18): p. 3624-3637. 321 100. nmrshiftdb2. Available from: http://nmrshiftdb.nmr.uni-koeln.de/ 101. Banfi, D. and L. Patiny, www.nmrdb.org: Resurrecting and Processing NMR Spectra On-line. CHIMIA International Journal for Chemistry, 2008. 62(4): p. 280-281.


84. Adamson, C.S. and E.O. Freed, Novel approaches to inhibiting HIV-1 replication. Antiviral Research, 2010. 85(1): p. 119-141.


85. Blum, A., et al., Achiral oligoamines as versatile tool for the development of aspartic protease inhibitors. Bioorganic & Medicinal Chemistry, 2008. 16(18): p. 8574-8586.