Anti-HBV nucleotide prodrug analogs: Synthesis, bioreversibility, and cytotoxicity studies

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 6, 2006, Pages 1491-1494

  Padmanabhan, Seetharamaiyer ^a   Coughlin, John E ^a   Zhang, Guangrong ^a   Kirk, Cassandra J ^a   Iyer, Radhakrishnan P ^a  

^a Spring Bank Pharmaceuticals Inc   (United States)

Author keywords

Anti HBV nucleotide; Bioreversibility; Cytotoxicity; Dinucleotide; Prodrug; Stability

Indexed keywords

ADENINE DERIVATIVE; ANTIVIRUS AGENT; DINUCLEOTIDE; NUCLEOTIDE DERIVATIVE; PRODRUG; URACIL DERIVATIVE;

ANIMAL CELL; ANTIVIRAL ACTIVITY; ARTICLE; CERCOPITHECIDAE; CONTROLLED STUDY; COW; CYTOTOXICITY TEST; DRUG DESIGN; DRUG MECHANISM; DRUG METABOLISM; DRUG STABILITY; HEPATITIS B VIRUS; HUMAN; HUMAN CELL; NONHUMAN; NUCLEOTIDE METABOLISM;

ADENINE; ANIMALS; ANTIVIRAL AGENTS; CATTLE; DRUG TOXICITY; HEPATITIS B VIRUS; OLIGODEOXYRIBONUCLEOTIDES; PHOSPHONIC ACIDS; PRODRUGS; RABBITS; REVERSE TRANSCRIPTASE INHIBITORS; SWINE; VIRUS REPLICATION;

ANIMALIA; CERCOPITHECIDAE; HEPATITIS B VIRUS;

EID: 32044456669     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.12.058     Document Type: Article

References (35)

1. H. Bundgaard In bio-reversible carriers in drug design E.B. Roche Theory and Application 1987 Pergamon Press New York 13
2. For excellent reviews see R. Oliyai, and V.J. Stella Annu. Rev. Pharmacol. Toxicol. 32 1993 521
3. S. Papot, I. Tranoy, F. Tillequin, J.-C. Florent, and J.-P. Gesson Curr. Med. Chem. -Anticancer Agents 2 2002 155
4. C. Tuerk, and L. Gold Science 249 1990 505
5. For a review: see S.D. Jayasena Clin. Chem. 45 1999 1628
6. For reviews see D.E. Szymkowski Drug Disc Today 1 1996 415
7. E. Uhlmann, and A. Peyman Chem. Rev. 90 1990 543
8. O.C. Uhlenbeck Nature 328 1987 596
9. P.D. Zamore Science 296 2002 1265
10. M. Manoharan Curr. Opin. Chem. Biol. 8 2004 570
11. R.P. Iyer, S. Kuchimanchi, and R.K. Pandey Drugs Future 28 2003 51
12. E. Uhlmann, and J. Vollmer Curr. Opin. Drug Discov. Dev. 6 2003 204
13. N.N. Polushin, and J.S. Cohen Nucleic Acids Res. 22 1994 5492
14. I. Barber, B. Rayner, and J.-L. Imbach Bioorg. Med. Chem. Lett. 5 1995 563
15. R.P. Iyer, N.-H. Ho, D. Yu, and S. Agrawal Bioorg. Med. Chem. Lett. 7 1997 871
16. R.W. Wagner, M.D. Matteucci, D. Grant, T. Huang, and B.C. Froehler Nat. Biotechnol. 14 1996 840
17. Reviewed in R.P. Iyer, S. Padmanabahan, G. Zhang, J.D. Morrey, and B.E. Korba Curr. Opin. Pharmacol. 5 2005 520
18. R.N. Hannoush, K.-L. Min, and M.J. Damha Nucleic Acids Res. 32 2004 6164
19. R.P. Iyer, Y. Jin, A. Roland, J.D. Morrey, S. Mounir, and B. Korba Antimicrob. Agents Chemother. 48 2004 2199
20. R.P. Iyer, A. Roland, Y. Jin, S. Mounir, B. Korba, J.G. Julander, and J.D. Morrey Antimicrob. Agents Chemother. 48 2004 2318
21. V. Nair Curr. Pharm. Des. 31 2003 2553
22. A.M. Rivkin Ann. Pharmacother. 38 2004 625
23. For a review see: D. Shan, M.G. Nicolaou, R.T. Borchardt, and B. Wang J. Pharm. Sci. 86 1997 765
24. R.A. Borchardt, and L.A. Cohen J. Am. Chem. Soc. 94 1972 9175
25. K.L. Amsberry, and R.T. Borchardt Pharm. Res. 8 1991 323
26. R.B. Greenwald, Y.H. Choe, C.D. Conover, K. Shum, D. Wu, and M. Royzen J. Med. Chem. 43 2000 475
27. For a review see S.L. Beaucage, and R.P. Iyer Tetrahedron 49 1993 1925
28. S. Padmanabhan, J.E. Coughlin, and R.P. Iyer Tetrahedron Lett. 46 2005 343
29. R.P. Iyer, J.E. Coughlin, and S. Padmanabhan Org. Prep. Proc. Intl. 37 2005 205
30. R.P. Iyer, J.B. Regan, W. Egan, and S.L. Beaucage J. Am. Chem. Soc. 112 1990 1253
31. S. Hayat, A.-U. Rahman, K.M. Khan, M.I. Choudhary, G.M. Maharvi, Z. Ullah, and E. Bayer Synth. Commun. 33 2003 2531
32. I. Fernàndez, B. Garcia, S. Muňoz, R. Pedro, and R. de la Salud Synlett 1993 489
33. R.P. Iyer, D. Yu, and S. Agrawal Bioorg. Med. Chem. Lett. 4 1995 2471
34. Interestingly 4-[N-methyl-N-(2,2,2-trifluroacetyr)amino]butyl phosphotriester undergoes base-catalyzed conversion to phosphodiesters via a novel cyclo-desterification reaction and has been employed in oligonucleotide synthesis. See: A. Wilk, A. Grajkowski, L.R. Phillips, and S.L. Beaucage J. Org. Chem. 64 1999 7515
35. p dinucleotide 5 was 13.5, 13.8 min. Cytotoxicity assays. Standard MTT assays were performed in 96-well plates using the Promega CellTiter96 Non-radioactive Cell Proliferation Assay Kit in conjunction with a 96-well Plate Reader (ThermoMax, Molecular devices), and MDBK, Vero, and HFF cell lines (obtained from ATCC). Several controls were employed including the nucleoside analogs 3TC, AZT, and ddC, as well as, media without drugs. SDS was used as a positive cytotoxic control. All pronucleotides were tested in triplicate at concentrations of 100, 300, and 1000 μM. Following a 24-h incubation of cells with the test substance, the MTT assay was carried out.