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

研究成果: Contribution to journalArticle査読

39 被引用数 (Scopus)


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.

ジャーナルBioorganic and Medicinal Chemistry
出版ステータス出版済み - 10 19 2000

All Science Journal Classification (ASJC) codes

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

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