Design of a Fluoro-olefin Cytidine Nucleoside as a Bioprecursor of a Mechanism-Based Inhibitor of Ribonucleotide Reductase

James R. McCarthy, Prasad S. Sunkara, Donald P. Matthews, Alan J. Bitonti, Esa T. Jarvi, Jeffrey S. Sabol, Robert J. Resvick, Edward W. Huber, Wilfred Adrianus van der Donk, Guixue Yu, Joanne Stubbe

Research output: Contribution to journalArticlepeer-review

Abstract

MDL 101,731 (3) is a fluoro olefin cytidine nucleoside designed as a bioprecursor of a mechanism-based inhibitor of ribonucleotide diphosphate reductase (RDPR) targeted for the treatment of tumors. The rationale for the use of a fluoro olefin in the design of 3 are discussed. A new stereospecific method to fluoro olefins was developed as a key step in the synthesis of MDL 101,731. Studies showing inactivation of both the R1 and R2 subunits of RDPR from E. coli by the diphosphate of MDL 101,731 are presented, and a proposed mechanism for the process is discussed. In addition, the antitumor profile of the drug is outlined. MDL 101,731 has recently entered clinical trials for the treatment of solid tumors in the US and Japan.

Original languageEnglish (US)
Pages (from-to)244-264
Number of pages21
JournalACS Symposium Series
Volume639
StatePublished - Dec 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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