3644 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
Kotra et al.
C. Synthesis and biological evaluation of 2′,3′-dideoxy-L-pyrimi-
dine nucleosides as potential antiviral agents against human
immunodeficiency virus (HIV) and hepatitis B virus (HBV). J .
Med. Chem. 1994, 37, 798-803.
283.0 (5319), 222.0 (11 141), 208.0 nm (4398) (pH 11.0); MS
(FAB) 304.0 (MH+). Anal. (C9H11F2N5O4‚0.5 H2O) C, H, N.
Ack n ow led gm en t. We thank Dr. Michael Bartlett
for providing the mass spectral analysis data. We
acknowledge the financial support of the NIH Grants
AI 32351 and AI 33655 and the Department of Veterans
Affairs. We thank Ms. Susan Schlueter-Wirtz, Angela
McMillan, and Sarah Kupfer for excellent technical
assistance.
(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-â-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-â-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-â-L-arabinofuranosyl uracil. Antimicrob. Agents Chemo-
ther. 1996, 40, 380-386.
(19) Tennant, B.; J acob, 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-â-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 hav-
ing 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) incorpora-
tion 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-â-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-ribo-
furanosyl nucleosides. J . Org. Chem. 1988, 52, 2406-2409.
(28) Szarek, W. A.; Depew, C.; J arrell, H. C.; J ones, J . K. N. J . Chem.
Soc., Chem. Commun. 1975, 648-649.
(29) Colorless prism crystal of orthorhombic system with the lattice
parameters: a ) 5.220(1) Å, b ) 15.034(2) Å, c ) 17.266(3) Å, V
) 1354.9(4) (Å)3; space group P212121.
(30) van Roey, P.; Pangborn, W. A.; Schinazi, R. F.; Painter, G.;
Liotta, D. C. (-)-cis-5-Fluoro-1-(2-(hydroxymethyl)-1,3-oxathi-
olan-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 struc-
ture 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 ., J r.; 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.
Su p p or tin g In for m a tion Ava ila ble: Tables of Anti-HIV,
1
anti-HBV, and anti-HSV activities and H and 13C NMR data
(8 pages). Ordering information is given on any current
masthead page.
Refer en ces
(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: Thera-
peutic 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 poly-
merases 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.; Yar-
choan, R.; Mitsuya, H. Emergence of human immunodeficiency
virus type
1 variants with resistance to multiple dideoxy
nucleosides in patients receiving therapy with dideoxy nucleo-
sides. 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) J eong, 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
â-L-(2R, 5S)- and R-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.; J eong, L. S.;
Beach, J . W.; Nampalli, K.; Cannon, D. L.; Chu, C. K. L-â-(2S,
4S)- and L-R-(2S, 4R)-Dioxolanyl nucleosides as potential anti-
HIV agents: Asymmetric synthesis and structure-activity rela-
tionships. J . Med. Chem. 1993, 36, 519-528.
(9) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.;
Cannon, D.; J eong, L. S.; Beach, J . W.; Choi, W.-B.; Yeola, S.;
Liotta, D. C. Activities of the four optical isomers of 2′,3′-dideoxy-
3′-thiacytidine (BCH-189) against human immunodeficiency
virus type 1 in human lymphocytes. Antimicrob. Agents Chemoth-
er. 1992, 36, 672-676.
(10) Beach, J . W.; J eong, 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 immunode-
ficiency virus (HIV). J . Org. Chem. 1992, 57, 2217-2219.
(11) Frick, L. W.; Lambe, C. U.; St. J ohn, 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.; Mathe´, C.;
Bergogne, M.-C.; Aubertin, A.-M.; Kiru, A.; Imbach, J .-L. Anti-
human immunodeficiency virus activities of the â-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.-
(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.
J M970275Y