Structure-activity relationships of 2'-deoxy-2',2'-difluoro-L-erythro- pentofuranosyl nucleosides

Journal of Medicinal Chemistry

Volumn 40, Issue 22, 1997, Pages 3635-3644

  Kotra, Lakshmi P ^a   Xiang, Yuejun ^a   Gary Newton, M ^b   Schinazi, Raymond F ^c,d   Cheng, Yung C ^e   Chu, Chung K ^a  

^a Department of Pharmacy and Toxicology   (United States)

^b UNIVERSITY OF GEORGIA   (United States)

^c ATLANTA VA MEDICAL CENTER   (United States)

^d EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CLEVUDINE; LAMIVUDINE; NUCLEOSIDE DERIVATIVE;

ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; ARTICLE; CYTOTOXICITY; DNA SYNTHESIS INHIBITION; DRUG EFFICACY; DRUG POTENCY; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN; STRUCTURE ACTIVITY RELATION; VIRUS STRAIN;

ANTIVIRAL AGENTS; CELLS, CULTURED; HEPATITIS B VIRUS; HERPESVIRUS 1, HUMAN; HERPESVIRUS 2, HUMAN; HIV-1; NUCLEOSIDES; SPECTRUM ANALYSIS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0030725747     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970275y     Document Type: Article

References (33)

1. Chu, C. K.; Baker, D. C., Eds. Nucleosides and Nucleotides as Antitumor agents and Antiviral Agents: Plenum Press: New York, 1993.
2. De Clercq, E. Toward improved anti-HIV chemotherapy: Therapeutic strategies for intervention with HIV infections. J. Med. Chem. 1995, 38, 2491-2517.
3. Martin, J. L.; Brown, C. E.; Mathews-Davis, N.; Reardon, J. E. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob. Agents Chemother. 1994, 38, 2743-2749.
4. Parker, W. B.; Cheng, Y. C. Mitochondrial toxicity of antiviral nucleoside analogs. J. NIH Res. 1994, 6, 57-61.
5. Shirasada, T.; Kavlick, M. F.; Veno, T.; Gao, W.-Y.; Kojima, E.; Alcaide, M. L.; Chokekijchai, S.; Roy, B. M.; Arnold, E.; Yarchoan, R.; Mitsuya, H. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxy nucleosides in patients receiving therapy with dideoxy nucleosides. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2398-2402.
6. Chatis, P. A.; Crumpacker, C. S. Resistance of herpes viruses to antiviral drugs. Antimicrob. Agents Chemother. 1992, 36, 1589-1595.
7. Jeong, L. S.; Schinazi, R. F.; Beach, J. W.; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves, A. J.; McMillan, A.; Chu, C. K.; Mathis, R. Asymmetric synthesis and biological evaluation of β-L-(2R, 5S)- and α-L-(2R, 5R)-1,3-oxathiolane-pyrimidine and-purine nucleosides as potential anti-HIV agents. J. Med. Chem. 1993, 36, 181-195.
8. Kim, H. O.; Schinazi, R. F.; Shanmuganathan, K.; Jeong, L. S.; Beach, J. W.; Nampalli, K.; Cannon, D. L.; Chu, C. K. L-β-(2S, 4S)- and L-α-(2S, 4R)-Dioxolanyl nucleosides as potential anti-HIV agents: Asymmetric synthesis and structure-activity relationships. J. Med. Chem. 1993, 36, 519-528.
9. Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.; Jeong, L. S.; Beach, J. W.; Choi, W.-B.; Yeola, S.; Liotta, D. C. Activities of the four optical isomers of 2′,3′-dideoxy3′-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob. Agents Chemother. 1992, 36, 672-676.
10. Beach, J. W.; Jeong, L. S.; Alves, A. J.; Pohl, D.; Kim, H. O.; Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. Synthesis of enantiomerically pure (2′R,5′S)-(-)-1,2-[2-(hydroxymethyl)oxathiolan-5-yl]cytosine as a potent antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV). J. Org. Chem. 1992, 57, 2217-2219.
11. Frick, L. W.; Lambe, C. U.; St. John, L.; Taylor, L. C.; Nelson, D. J. Pharmacokinetics, oral bioavailability, and metabolism in mice and Cynomolgus monkeys of (2′R,5′S)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, as agent active against human immunodeficiency virus and human hepatitis B virus. Antimicrob. Agents Chemother. 1994, 38, 2722-2729.
12. Lin, T.-S.; Luo, M.-Z.; Liu, M.-C. Synthesis of several pyrimidine L-nucleoside analogs as potential antiviral agents. Tetrahedron 1995, 51, 1055-1068.
13. Lin, T.-S.; Luo, M.-Z.; Zhu, J. L.; Liu, M.-C.; Zhu, Y. L.; Dutschman, G. E.; Cheng, Y.-C. Synthesis of a series of purine 2′,3′-dideoxy-L-nucleoside analogs as potential antiviral agents. Nucleosides Nucleotides 1995, 14, 1759-1793.
14. Gosselin, G.; Schinazi, R. F.; Sommadossi, J.-P.; Mathé, C.; Bergogne, M.-C.; Aubertin, A.-M.; Kiru, A.; Imbach, J.-L. Anti-human immunodeficiency virus activities of the β-L-enantiomer of 2′,3′-dideoxy cytidine and its 5-fluoro derivative in vitro. Antimicrob. Agents Chemother. 1994, 38, 1292-1297.
15. Lin, T. S.; Luo, M. Z.; Pai, S. B.; Dutschman, G. E.; Cheng, Y.- C. Synthesis and biological evaluation of 2′,3′-dideoxy-L-pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). J. Med. Chem. 1994, 37, 798-803.
16. Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, J. S.; Shanmuganathan, K.; Du, J. F.; Wang, C. W.; Kim, H.; Newton, M. G.; Cheng, Y.-C.; Chu, C. K. Structure-activity relationships of 1-(2-deoxy-2-fluoro-β-L-arabinofuranosyl) pyrimidine nucleosides as anti-hepatitis B virus agents. J. Med. Chem. 1996, 39, 2835-2843
17. Chu, C. K.; Ma, T. W.; Shanmuganathan, K.; Wang, C. G.; Xiang Y. J.; Pai, S. B.; Yao, G. Q.; Sommadossi, J.-P.; Cheng, Y.-C. Use of 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus. Antimicrob. Agents Chemother. 1995, 39, 979-981.
18. Pai, S. B.; Liu, S. H.; Zhu, Y. L.; Chu, C. K.; Cheng. Y. C. Inhibition of hepatitis-B virus by a novel L-nucleoside, 2′-fluoro-5-methyl-β-L-arabinofuranosyl uracil. Antimicrob. Agents Chemother. 1996, 40, 380-386.
19. Tennant, B.; Jacob, J.; Graham, L. A.; Peek, S.; Korba, B.; Gerin, J. L.; Witcher, J. W.; Boudinot, F. D.; Du, J.; Chu, C. K. Pharmacokinetic and pharmacodynamic studies of 1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)uracil (L-FAMU) in the Wood-chuck Model of Hepatitis B virus (HBV) infection. Antiviral Res. 1997, 34 (2), A52.
20. Hertel, L. W.; Kroin, J. S. 2′-Deoxy-2′,2′-difluoro-(4-substituted pyrimidine) nucleosides having antiviral and anti-cancer activity and intermediates. Eur. Pat. Appl. EP 576,230 1993; Chem. Abstr. 1993, 121, 57886q.
21. Grindey, G. B.; Grossman, C. S.; Hertel, L. W.; Kroin, J. S. 2′-Deoxy-2′,2′-difluoro-(2,6,8-substituted) purine nucleosides having antiviral and anticancer activity and intermediates. Eur. Pat. Appl. EP 576,227 1993; Chem. Abstr. 1993, 121, 57887r.
22. Plunkett, W.; Gandhi, V.; Chubb, C.; Nowak, B.; Heinemann, V.; Mineishi, S.; Sen, A.; Hertel, L. W.; Grindey, G. B. 2′,2′-Difluorodeoxycytidine metabolism and mechanism of action in human leukemia cells. Nucleosides Nucleotides 1989, 8, 775-785.
23. Ruiz, V. W. T.; Haperen, V.; Veerman, G.; Vermorken, J. B.; Peters, G. J. 2′,2′-Difluorodeoxycytidine (gemcitabine) incorporation into RNA and DNA of tumor cell lines. Biochem. Pharmacol. 1993, 46, 762-766.
24. Gandhi, V.; Mineishi, S.; Huang, P.; Chapman, A. J.; Young, Y.; Chen, F.; Nowak, B.; Chubb, S.; Hertel, L. W.; Plunkett, W. Cytotoxicity, metabolism and mechanism of action of 2′,2′-difluorodeoxy guanosine in Chinese Hamster Ovary cells. Cancer Res. 1995, 55, 1517-1524.
25. Xiang, Y. J.; Kotra, L. P.; Chu, C. K. Synthesis and anti-HIV activities of 2′-deoxy-2′,2″- difluoro-β-L-ribofuranosyl-pyrimidine and -purine nucleosides. Bioorg. Med. Chem. Lett. 1995, 5, 743-748.
26. Hubschwerlen, C. A convenient synthesis of L-(S)-glyceralde-hydeacetonide from L-ascorbic acid. Synthesis 1986, 962.
27. Hertel, L. W.; Kroin, J. S.; Missner, J. W.; Tustin, J. M. Synthesis of 2-deoxy-2,2-difluoro-D-ribose and 2-deoxy-2,2-difluoro-D-ribofuranosyl nucleosides. J. Org. Chem. 1988, 52, 2406-2409.
28. Szarek, W. A.; Depew, C.; Jarrell, H. C.; Jones, J. K. N. J. Chem. Soc., Chem. Commun. 1975, 648-649.
29. 1.
30. van Roey, P.; Pangborn, W. A.; Schinazi, R. F.; Painter, G.; Liotta, D. C. (-)-cis-5-Fluoro-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine absolute configuration, antiviral agent against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus. Antiviral Chem. Chemother. 1993, 4, 369.
31. Molecules were overlapped using "Fit Atoms" module in SYBYL (Tripos Associates Inc., St. Louis, MO) and the modeling was performed on a Silicon Graphics Indy workstation. X-ray structure of (-)-FTC was obtained from Cambridge Structural Database and that of L-FAMU was performed in our laboratories. The X-ray structures were not relaxed through minimization before fitting and the "fit" was performed by overlaping N1, C1′, and C4′ atoms or the corresponding atoms of the each molecule.
32. Marquez, V. E.; Lin, B. B.; Barchi, J. J., Jr.; Nicklaus, M. C. Conformational studies and anti-HIV activity of mono- and difluorodideoxy nucleosides. In Nucleosides and nucleotides as antitumor and antiviral agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993; pp 265-283.
33. van Roey, P.; Chu, C. K. Crystal structures and molecular conformations of anti-HIV nucleosides. In: Nucleosides and nucleotides as antitumor and antiviral agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993; pp 285-302.