2′-Deoxy-2′-methylenecytidine and 2′-Deoxy-2′,2′-difluorocytidine 5′-Diphosphates: Potent Mechanism-Based Inhibitors of Ribonucleotide Reductase

It has been found that 2′-deoxy-2′-methyleneuridine (MdUrd), 2′-deoxy-2′-methylenecytidine (MdCyd), and 2′- deoxy-2′,2′-difluorocytidine (dFdCyd) 5′-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3′ to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3′ to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd find dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.