[摘要]：A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N6-substituted derivs. of the antitumor agent 3'-C-methyladenosine (3'-Me-Ado), an inhibitor of the a Rnr1 subunit of mammalian ribonucleotide reductase (RR), were synthesized. The cytotoxicity of these compds. was evaluated against a panel of human leukemia and carcinoma cell lines and compared to that of some corresponding N6-substituted adenosine analogs. N6-cycloalkyl-3'-C-methylribonucleosides, e.g. I (R = cyclobutyl), and N6-Ph analog I (R = Ph) inhibit the proliferation of K562 leukemia cells. N6-(?-endo-2-norbornyl-3'-C-methyladenosine was the most cytotoxic compd., with GI50 values slightly higher than that of 3'-Me-Ado against K562 and carcinoma cell lines and 2.7 fold higher cytotoxicity against human promyelocytic leukemia HL-60 cells. The SAR study confirms that an unsubstituted N6-amino group is essential for optimal cytotoxicity of 3'-Me-Ado against both K562 and carcinoma cell lines. Computational studies, carried out on the eukaryotic a subunit (Rnr1) of RR from Saccharomyces cerevisiae were performed to rationalize the obsd. structure-activity relationships. The antitumor activity of the new 3'-C-methyladenosine derivs. substituted in the N-amino group was evaluated in human myelogenous leukemia K562, human colon adenocarcinoma CaCo-2, human colon carcinoma HT-29, and human breast carcinoma MCF-7 cell lines.
