Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors.: Synthesis, antitumor activity, and molecular modeling of N6-substituted 3'-C-methyladenosine derivatives

A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N-6-substituted derivatives 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 compounds was evaluated against a panel of human leukemia and carcinoma cell lines and compared to that of some corresponding N6-substituted adenosine analogues. N-6-cycloalkyl-3'-C-methylribonucleosides 2-7 and N-6-phenyl analogue 8 were found to inhibit the proliferation of K562 leukemia cells. N6-(+/-)-endo-2-norbornyl-3'-C-methyladenosine (7) was found to be the most cytotoxic compound, with GI(50) 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 N-6-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 observed structure-activity relationships.