期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 47, 期 -, 页码 167-174出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.10.039
关键词
Purine nucleoside phosphorylase; Organozinc halides; Cross-coupling reactions; 6-Alkyl; Cycloalkyl/aryl/heterocyclylpurine ribonucleosides
资金
- National Cancer Institute [U19CA67763]
A series of C-6 alkyl, cycloalkyl, and aryl-9-(beta-D-ribofuranosyl)purines were synthesized and their substrate activities with Escherichia colt purine nucleoside phosphorylase (E. coli PNP) were evaluated. (Ph3P)(4)Pd-mediated cross-coupling reactions of 6-chloro-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-purine (6) with primary alkyl (Me, Et, n-Pr, n-Bu, isoBu) zinc halides followed by treatment with NH3/MeOH gave the corresponding 6-alkyl-9-(beta-D-ribofuranosyl)purine derivatives 7-11, respectively, in good yields. Reactions of 6 with cycloalkyl(propyl, butyl, pentyl)zinc halides and aryl (phenyl, 2-thienyl)zinc halides gave under similar conditions the corresponding 6-cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and thienyl -9-(beta-D-ribofuranosyl)purine derivatives 12-16, respectively in high yields. E. colt PNP showed a high tolerance to the steric and hydrophobic environment at the 6-position of the synthesized purine ribonucleosides. Significant cytotoxic activity was observed for 8, 12, 15, and 16. Evaluation of 12 and 16 against human tumor xenografts in mice did not demonstrate any selective antitumor activity. In addition, 6-methyl-9-(beta-D-arabinofuranosyl)purine (18) was prepared and evaluated. (C) 2011 Elsevier Masson SAS. All rights reserved.
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