Ribose-Modified Purine Nucleosides as Ribonucleotide Reductase Inhibitors. Synthesis, Antitumor Activity, and Molecular Modeling of N 6-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 α 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 N 6-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. N 6-(±)-endo-2-norbornyl-3′-C-methyladenosine (7) was found to be the most cytotoxic compound, 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 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 α subunit (Rnr1) of RR from Saccharomyces cerevisiae were performed to rationalize the observed structure−activity relationships.