Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6-naphthyridine-7-carboxamide as a promising scaffold with drug-like properties

Journal of Medicinal Chemistry

Volumn 55, Issue 22, 2012, Pages 9492-9509

  Zeng, Li Fan ^a   Wang, Yong ^a   Kazemi, Roza ^b   Xu, Shili ^b   Xu, Zhong Liang ^a   Sanchez, Tino W ^b   Yang, Liu Meng ^c   Debnath, Bikash ^b   Odde, Srinivas ^b   Xie, Hua ^a   Zheng, Yong Tang ^c   Ding, Jian ^a   Neamati, Nouri ^b   Long, Ya Qiu ^a  

^a Chinese Academy of Sciences   (China)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^c KUNMING INSTITUTE OF ZOOLOGY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

1,6 NAPHTHYRIDINE 7 CARBOXAMIDE; 4 AMINO 7 TERT BUTYL 5 (4 CHLOROPHENYL)PYRAZOLO[3,4 D]PYRIMIDINE; ANTIRETROVIRUS AGENT; INTEGRASE INHIBITOR; LAPATINIB; N (4 FLUOROBENZYL) 8 HYDROXY 5 (TETRAHYDRO 2H 1,2 THIAZIN 2 YL) 1,6 NAPHTHYRIDINE 7 CARBOXAMIDE S,S DIOXIDE; SUNITINIB; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; ARTICLE; CANCER CELL CULTURE; CELL PROLIFERATION; CONTROLLED STUDY; CYTOTOXICITY; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN TISSUE; IC 50;

ANTINEOPLASTIC AGENTS; DRUG DESIGN; HIV INFECTIONS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NAPHTHYRIDINES; NEOPLASMS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED; VIRUS INTEGRATION;

EID: 84870052593     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300667v     Document Type: Article

References (44)

1. Ashburn, T. T.; Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs Nature Rev. Drug Discovery 2004, 3, 673-683
2. Boguski, M. S.; Mandl, K. D.; Sukhatme, V. P. Drug discovery. Repurposing with a difference Science 2009, 324, 1394-1395
3. Andronis, C.; Sharma, A.; Virvilis, V.; Deftereos, S.; Persidis, A. Literature mining, ontologies and information visualization for drug repurposing Briefings Bioinf. 2011, 12, 357-368
4. Dudley, J. T.; Deshpande, T.; Butte, A. J. Exploiting drug-disease relationships for computational drug repositioning Briefings Bioinf. 2011, 12, 303-311
5. Haupt, V. J.; Schroeder, M. Old friends in new guise: repositioning of known drugs with structural bioinformatics Briefings Bioinf. 2011, 12, 312-326
6. Hazuda, D. J.; Young, S. D.; Guare, J. P.; Anthony, N. J.; Gomez, R. P.; Wai, J. S.; Vacca, J. P.; Handt, L.; Motzel, S. L.; Klein, H. J.; Dornadula, G.; Danovich, R. M.; Witmer, M. V.; Wilson, K. A. A.; Tussey, L.; Schleif, W. A.; Gabryelski, L. S.; Jin, L. X.; Miller, M. D.; Casimiro, D. R.; Emini, E. A.; Shiver, J. W. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques Science 2004, 305, 528-532
7. Hazuda, D. J.; Anthony, N. J.; Gomez, R. P.; Jolly, S. M.; Wai, J. S.; Zhuang, L.; Fisher, T. E.; Embrey, M.; Guare, J. P., Jr.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.; Felock, P. J.; Witmer, M. V.; Stillmock, K. A.; Danovich, R.; Grobler, J.; Miller, M. D.; Espeseth, A. S.; Jin, L.; Chen, I. W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.; Wong, B. K.; Xu, W.; Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.; Holloway, M. K.; Young, S. D. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11233-11238
8. Plasencia, C.; Dayam, R.; Wang, Q.; Pinski, J.; Burke, T. R., Jr.; Quinn, D. I.; Neamati, N. Discovery and preclinical evaluation of a novel class of small-molecule compounds in hormone-dependent and -independent cancer cell lines Mol. Cancer Ther. 2005, 4, 1105-1113
9. Cao, X.; Plasencia, C.; Kanzaki, A.; Yang, A.; Burke, T. R., Jr.; Neamati, N. Elucidation of the molecular mechanisms of a salicylhydrazide class of compounds by proteomic analysis Curr. Cancer Drug Targets 2009, 9, 189-201
10. Thompson, A. M.; Connolly, C. J.; Hamby, J. M.; Boushelle, S.; Hartl, B. G.; Amar, A. M.; Kraker, A. J.; Driscoll, D. L.; Steinkampf, R. W.; Patmore, S. J.; Vincent, P. W.; Roberts, B. J.; Elliott, W. L.; Klohs, W.; Leopold, W. R.; Showalter, H. D.; Denny, W. A. 3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7- diamines and related 2-urea derivatives are potent and selective inhibitors of the FGF receptor-1 tyrosine kinase J. Med. Chem. 2000, 43, 4200-4211
11. Thompson, A. M.; Delaney, A. M.; Hamby, J. M.; Schroeder, M. C.; Spoon, T. A.; Crean, S. M.; Showalter, H. D.; Denny, W. A. Synthesis and structure-activity relationships of soluble 7-substituted 3-(3,5- dimethoxyphenyl)-1,6-naphthyridin-2-amines and related ureas as dual inhibitors of the fibroblast growth factor receptor-1 and vascular endothelial growth factor receptor-2 tyrosine kinases J. Med. Chem. 2005, 48, 4628-4653
12. Zartman, C. B.; Bell, I. M.; Gallicchio, S. N.; Graham, S. L.; Kane, S. A.; Mallee, J. J.; Rutledge, R. Z.; Salvatore, C. A.; Vacca, J. P.; Williams, T. M. Identification of a novel RAMP-independent CGRP receptor antagonist Bioorg. Med. Chem. Lett. 2011, 21, 6705-6708
13. Neamati, N. HIV-1 Integrase: Mechanism and Inhibitor Design; Wiley: New York, 2011.
14. Pendri, A.; Meanwell, N. A.; Peese, K. M.; Walker, M. A. New first and second generation inhibitors of human immunodeficiency virus-1 integrase Expert Opin. Ther. Pat. 2011, 21, 1173-1189
15. Egbertson, M.; Anthony, N. J.; Vincenzo Summa, V. HIV Integrase Inhibitors: From Diketoacids to Heterocyclic Templates: A History of HIV Integrase Medicinal Chemistry at Merck West Point and Merck Rome (IRBM) Leading to the Discovery of Raltegravir; In HIV-1 Integrase: Mechanism and Inhibitor Design. Ed (Neamati, N). Wiley: New York, 2011.
16. Egbertson, M. S. HIV integrase inhibitors: from diketoacids to heterocyclic templates: a history of HIV integrase medicinal chemistry at Merck West Point and Merck Rome (IRBM) Curr. Top. Med. Chem. 2007, 7, 1251-1272
17. Egbertson, M. S.; Moritz, H. M.; Melamed, J. Y.; Han, W.; Perlow, D. S.; Kuo, M. S.; Embrey, M.; Vacca, J. P.; Zrada, M. M.; Cortes, A. R.; Wallace, A.; Leonard, Y.; Hazuda, D. J.; Miller, M. D.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Schleif, W.; Gabryelski, L. J.; Moyer, G.; Ellis, J. D.; Jin, L.; Xu, W.; Braun, M. P.; Kassahun, K.; Tsou, N. N.; Young, S. D. A potent and orally active HIV-1 integrase inhibitor Bioorg. Med. Chem. Lett. 2007, 17, 1392-1398
18. Embrey, M. W.; Wai, J. S.; Funk, T. W.; Homnick, C. F.; Perlow, D. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Jin, L.; Chen, I. W.; Ellis, J. D.; Wong, B. K.; Lin, J. H.; Leonard, Y. M.; Tsou, N. N.; Zhuang, L. A series of 5-(5,6)-dihydrouracil substituted 8-hydroxy-[1,6]naphthyridine-7- carboxylic acid 4-fluorobenzylamide inhibitors of HIV-1 integrase and viral replication in cells Bioorg. Med. Chem. Lett. 2005, 15, 4550-4554
19. Espeseth, A. S.; Felock, P.; Wolfe, A.; Witmer, M.; Grobler, J.; Anthony, N.; Egbertson, M.; Melamed, J. Y.; Young, S.; Hamill, T.; Cole, J. L.; Hazuda, D. J. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 11244-11249
20. Guare, J. P.; Wai, J. S.; Gomez, R. P.; Anthony, N. J.; Jolly, S. M.; Cortes, A. R.; Vacca, J. P.; Felock, P. J.; Stillmock, K. A.; Schleif, W. A.; Moyer, G.; Gabryelski, L. J.; Jin, L.; Chen, I. W.; Hazuda, D. J.; Young, S. D. A series of 5-aminosubstituted 4-fluorobenzyl-8-hydroxy-[1,6]naphthyridine-7- carboxamide HIV-1 integrase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 2900-2904
21. Gudmundsson, K. S.; Johns, B. A.; Weatherhead, J. Pyrazolopyrimidines and pyrazolotriazines with potent activity against herpesviruses Bioorg. Med. Chem. Lett. 2009, 19, 5689-5692
22. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.; Jeffrey, J. L.; Miller, W. H. The use of oxadiazole and triazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 1: Establishing the pharmacophore Bioorg. Med. Chem. Lett. 2009, 19, 1802-1806
23. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.; Jeffrey, J. L.; Miller, W. H. 1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position Bioorg. Med. Chem. Lett. 2009, 19, 1807-1810
24. Melamed, J. Y.; Egbertson, M. S.; Varga, S.; Vacca, J. P.; Moyer, G.; Gabryelski, L.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Schleif, W.; Hazuda, D. J.; Leonard, Y.; Jin, L.; Ellis, J. D.; Young, S. D. Synthesis of 5-(1-H or 1-alkyl-5-oxopyrrolidin-3-yl)-8-hydroxy-[1,6]-naphthyridine-7- carboxamide inhibitors of HIV-1 integrase Bioorg. Med. Chem. Lett. 2008, 18, 5307-5310
25. Wai, J. S.; Egbertson, M. S.; Payne, L. S.; Fisher, T. E.; Embrey, M. W.; Tran, L. O.; Melamed, J. Y.; Langford, H. M.; Guare, J. P., Jr.; Zhuang, L.; Grey, V. E.; Vacca, J. P.; Holloway, M. K.; Naylor-Olsen, A. M.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.; Schleif, W. A.; Gabryelski, L. J.; Young, S. D. 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells J. Med. Chem. 2000, 43, 4923-4926
26. Wai, J. S.; Kim, B.; Fisher, T. E.; Zhuang, L.; Embrey, M. W.; Williams, P. D.; Staas, D. D.; Culberson, C.; Lyle, T. A.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Schleif, W. A.; Gabryelski, L. J.; Jin, L.; Chen, I. W.; Ellis, J. D.; Mallai, R.; Young, S. D. Dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors Bioorg. Med. Chem. Lett. 2007, 17, 5595-5599
27. Wiscount, C. M.; Williams, P. D.; Tran, L. O.; Embrey, M. W.; Fisher, T. E.; Sherman, V.; Homnick, C. F.; Donnette Staas, D.; Lyle, T. A.; Wai, J. S.; Vacca, J. P.; Wang, Z.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Miller, M. D.; Hazuda, D. J.; Day, A. M.; Gabryelski, L. J.; Ecto, L. T.; Schleif, W. A.; DiStefano, D. J.; Kochansky, C. J.; Anari, M. R. 10-Hydroxy-7,8- dihydropyrazino[1′,2′:1,5]pyrrolo[2,3- d ]pyridazine-1,9(2 H,6 H)-diones: potent, orally bioavailable HIV-1 integrase strand-transfer inhibitors with activity against integrase mutants Bioorg. Med. Chem. Lett. 2008, 18, 4581-4583
28. Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.; Egbertson, M. S.; Payne, L. S.; Guare, J. P., Jr.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Leonard, Y. M.; Lynch, J. J., Jr.; Michelson, S. R.; Young, S. D. Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells J. Med. Chem. 2003, 46, 453-456
29. Chan, L.; Jin, H.; Stefanac, T.; Lavallee, J. F.; Falardeau, G.; Wang, W.; Bedard, J.; May, S.; Yuen, L. Discovery of 1,6-naphthyridines as a novel class of potent and selective human cytomegalovirus inhibitors J. Med. Chem. 1999, 42, 3023-3025
30. Chan, L.; Stefanac, T.; Lavallee, J. F.; Jin, H.; Bedard, J.; May, S.; Falardeau, G. Design and synthesis of new potent human cytomegalovirus (HCMV) inhibitors based on internally hydrogen-bonded 1,6-naphthyridines Bioorg. Med. Chem. Lett. 2001, 11, 103-105
31. Falardeau, G.; Lachance, H.; St-Pierre, A.; Yannopoulos, C. G.; Drouin, M.; Bedard, J.; Chan, L. Design and synthesis of a potent macrocyclic 1,6-naphthyridine anti-human cytomegalovirus (HCMV) inhibitors Bioorg. Med. Chem. Lett. 2005, 15, 1693-1695
32. Anthony, N. J.; Gomez, R. P.; Young, S. D.; Egbertson, M.; Wai, J. S.; Zhuang, L.; Embrey, M.; Tran, L.; Melamed, J. Y.; Langford, H. M.; Guare, J. P.; Fisher, T. E.; Jolly, S. M.; Kuo, M. S.; Perlow, D. S.; Bennett, J. J.; Funk, T. W. Preparation of (Poly)azanaphthalenyl carboxamides as HIV Integrase Inhibitors. Patent WO 2002/030930 A2 2002.
33. Pommier, Y.; Johnson, A. A.; Marchand, C. Integrase inhibitors to treat HIV/AIDS Nature Rev. Drug Discovery 2005, 4, 236-248
34. Hare, S.; Gupta, S. S.; Valkov, E.; Engelman, A.; Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer Nature 2010, 464, 232-236
35. Hare, S.; Vos, A. M.; Clayton, R. F.; Thuring, J. W.; Cummings, M. D.; Cherepanov, P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20057-20062
36. Millipore UK Corporation web site: www.millipore.com.
37. Wang, R. R.; Gao, Y. D.; Ma, C. H.; Zhang, X. J.; Huang, C. G.; Huang, J. F.; Zheng, Y. T. Mangiferin, an anti-HIV agent targeting protease and effective against resistant strains. Molecules 2011, 16, 4264-4277
38. Fan, X.; Zhang, F. H.; Al-Safi, R. I.; Zeng, L. F.; Shabaik, Y.; Debnath, B.; Sanchez, T. W.; Odde, S.; Neamati, N.; Long, Y. Q. Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups Bioorg. Med. Chem. 2011, 19, 4935-4952
39. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking J. Mol. Biol. 1997, 267, 727-748
40. Jones, G.; Willett, P. Docking small-molecule ligands into active sites Curr. Opin. Biotechnol. 1995, 6, 652-656
41. LigPrep, version 2.5; Schrödinger, LLC: New York, 2011.
42. Epik, version 2.2; Schrödinger, LLC: New York, 2011.
43. Carmichael, J.; DeGraff, W. G.; Gazdar, A. F.; Minna, J. D.; Mitchell, J. B. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing Cancer Res. 1987, 47, 936-942
44. Munshi, A.; Hobbs, M.; Meyn, R. E. Clonogenic cell survival assay Methods Mol. Med. 2005, 110, 21-28