Synthesis and evaluation of multisubstrate analogue inhibitors of purine nucleoside phosphorylases

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

Research output: Contribution to journalArticle

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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

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Purine-Nucleoside Phosphorylase
Isomers
Inhibitory Concentration 50
Phosphates
Inosine
Stereochemistry
Phosphorylation
Cyclization
Nucleotides
Erythrocytes
Substrates
purine
1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acid

All Science Journal Classification (ASJC) codes

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

Cite this

Synthesis and evaluation of multisubstrate analogue inhibitors of purine nucleoside phosphorylases. / Yokomatsu, Tsutomu; Hayakawa, Yoshinobu; Kihara, Taro; Satoru, Koyanagi; Soeda, Shinji; Shimeno, Hiroshi; Shibuya, Shiroshi.

In: Bioorganic and Medicinal Chemistry, Vol. 8, No. 11, 19.10.2000, p. 2571-2579.

Research output: Contribution to journalArticle

Yokomatsu, Tsutomu ; Hayakawa, Yoshinobu ; Kihara, Taro ; Satoru, Koyanagi ; Soeda, Shinji ; Shimeno, Hiroshi ; Shibuya, Shiroshi. / Synthesis and evaluation of multisubstrate analogue inhibitors of purine nucleoside phosphorylases. In: Bioorganic and Medicinal Chemistry. 2000 ; Vol. 8, No. 11. pp. 2571-2579.
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