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

C. H. Baker, J. Banzon, J. M. Bollinger, J. Stubbe, V. Samano, M. J. Robins, B. Lippert, E. Jarvi, R. Resvick

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230 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1879-1884
Number of pages6
JournalJournal of Medicinal Chemistry
Volume34
Issue number6
DOIs
StatePublished - Jun 1 1991

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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