This investigation has as its goal the design and synthesis of a series of potential anticancer and antiviral nucleoside analogues, the evaluation of their biological activities both in vitro and in vivo in tumor-bearing and virus infected animals, and the elucidation of the biochemical mechanism of action(s) of their biological activity. The approaches to be employed include the development of methodology for the preparation of these nucleoside analogues, their characterization by NMR, UV, mass spectrum, and other spectrometric techniques, and the determination of their anticancer and antiviral activities in cell culture and in animal models. Recently, the synthesis and antineoplastic evaluation of several new 3'-azido and 3'-amino nucleoside analogues have been carried out in this laboratory. Among these compounds, 3'-amino-2', 3'dideoxycytidine (3'-NH2-CdR, NSC 365107) has shown potent inhibitory effects against L1210, P388 and Sarcoma 180 cells in vitro. The cytotoxicity was selectively prevented by 2'- deoxycytidine, and not by other pyrimidine deoxyribo- or ribonucleosides, or purine nucleosides. More importantly, the 3'- amino analogue of 2'-deoxycytidine exhibits marked anticancer activity against both L1210 and P388 leukemias in mice. Thus when given in a dose of 20 mg/Kg twice a day for nine consecutive days to animals bearing the L1210 leukemia, 3'-NH2- CdR produced cures in 80% of the treated animals, and this regimen yielded a T/C X 100 value of 200 in mice bearing the P388 leukemia. 3'-NH2-CdR is resistant to deamination by purified cytidine-deoxycytidine deaminase derived from human KB cells; both cytidine and 2'-deoxycytidine are readily deaminated by this enzyme system. Based on these findings, the fabrication and chemotherapeutic testing of a novel series of nucleoside analogues are proposed in which the sugar portion is modified and the base moeity varied. The molecular basis for the activity of those compounds that are biologically active will be determined.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045410-03
Application #
3188511
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1987-08-01
Project End
1991-07-31
Budget Start
1989-08-01
Budget End
1991-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Lin, T S; Schinazi, R; Griffith, B P et al. (1989) Selective inhibition of human immunodeficiency virus type 1 replication by the (-) but not the (+) enantiomer of gossypol. Antimicrob Agents Chemother 33:2149-51
Simpson, M V; Chin, C D; Keilbaugh, S A et al. (1989) Studies on the inhibition of mitochondrial DNA replication by 3'-azido-3'-deoxythymidine and other dideoxynucleoside analogs which inhibit HIV-1 replication. Biochem Pharmacol 38:1033-6
Lin, T S; Shen, Z Y; August, E M et al. (1989) Synthesis and antiviral activity of several 2,5'-anhydro analogues of 3'-azido-3'-deoxythymidine, 3'-azido-2',3'-dideoxyuridine, 3'-azido-2',3'-dideoxy-5-halouridines, and 3'-deoxythymidine against human immunodeficiency virus and Rauscher-murine leukemia J Med Chem 32:1891-5
Mancini, W R; Williams, M S; Lin, T S (1988) Specific inhibition of DNA biosynthesis induced by 3'-amino-2',3'-dideoxycytidine. Biochemistry 27:8832-9
Lin, T S; Guo, J Y; Schinazi, R F et al. (1988) Synthesis and antiviral activity of various 3'-azido analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1, HTLV-III/LAV). J Med Chem 31:336-40
Lin, T S; Zhang, X H; Wang, Z H et al. (1988) Synthesis and antiviral evaluation of carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine. J Med Chem 31:484-6