NUCLEOSIDES AND NUCLEOTIDES - 175 - STRUCTURAL REQUIREMENTS OF THE SUGAR MOIETY FOR THE ANTITUMOR ACTIVITIES OF NEW NUCLEOSIDE ANTIMETABOLITES, 1-(3-C-ETHYNYL-BETA-D-RIBO-PENTOFURANOSYL)CYTOSINE AND 1-(3-C-ETHYNYL-BETA-D-RIBO-PENTOFURANOSYL)URACIL

We previously designed 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uraci l (EUrd) and its cytosine congener (ECyd) as potential multifunctional antitumor nucleoside antimetabolites. They showed potent and broad-sp ectrum antitumor activity against various human and mouse tumor cells in vitro and in vivo. To clarify the structure-activity relationship o f the sugar moiety, various 3'-C-carbon-substituted analogues, such as 1-propynyl, 1-butynyl, ethenyl, ethyl, and cyclopropyl derivatives, o f ECyd and EUrd were synthesized. We also prepared 3'-deoxy analogues and 3'-homologues of ECyd and EUrd with different configurations to de termine the role of the 3'-hydroxyl group and the length between the S '-carbon atom and the ethynyl group and a 2'-ethynyl derivative of ECy d to determine the spatial requirements of the ethynyl group. The in v itro tumor cell growth inhibitory activities of these nucleosides agai nst mouse leukemic L1210 and human KB cells showed that ECyd and EUrd were the most potent inhibitors in the series, with IC50 values of 0.0 16 and 0.13 mu M for L1210 cells and 0.028 and 0.029 mu M for KB cells , respectively. Only 3'-C-1-propynyl and -ethenyl derivatives of ECyd showed greatly reduced cytotoxicity. We found that the cytotoxic activ ity of these nucleosides predominantly depended on their first phospho rylation by uridine/cytidine kinase.