Synthesis and evaluation of multisubstrate analogue inhibitors of purine nucleoside phosphorylases

Tsutomu Yokomatsu, Yoshinobu Hayakawa, Taro Kihara, Satoru Koyanagi, Shinji Soeda, Hiroshi Shimeno, Shiroshi Shibuya

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39 Citations (Scopus)

Abstract

1,1-Difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids (±)-cis-4a and (±)-trans-4a possessing a (purine-9-yl)methyl functionality at the ring as well as their homologues (±)-cis-4b and (±)-trans-4b were synthesized and tested as 'multi-substrate analogue' inhibitors for purine nucleoside phosphorylases. Radical cyclization of allylic α,α-difluorophosphonates 8a,b was applied to construct the α,α-difluorophosphonate-functionalized oxacycles 9a,b. The IC50 values of the nucleotide analogues (±)-cis-4a and (±)-cis-4b were 88 and 38nM, respectively, for human erythrocyte PNP-catalyzed phosphorylation of inosine in the presence of 100mM orthophosphate. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency. The trans-isomers (±)-trans-4a and (±)-trans-4b were ca. 4-fold less potent than the corresponding cis-isomers. At an intracellular concentration of orthophosphate (1mM), (±)-cis-4b, the most potent compound of this series, was shown to have IC50 and K(i) values of 8.7 and 3.5nM, respectively. Copyright (C) 2000 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)2571-2579
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume8
Issue number11
DOIs
Publication statusPublished - Oct 19 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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