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.
