Synthesis, conformational analysis, and biological activity of C- thioribonucleosides related to tiazofurin

Palmarisa Franchetti, Stefano Marchetti, Loredana Cappellacci, Hiremagalur N. Jayaram, Joel Aaron Yalowitz, Barry M. Goldstein, Jean Louis Barascut, David Dukhan, Jean Louis Imbach, Mario Grifantini

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Abstract

The syntheses of furanthiofurin [5β-D-(4'-thioribofuranosyl)furan-3- carboxamide, 1] and thiophenthiofurin [5β-D-(4'-thioribofuranosyl)thiophene- 3-carboxamide, 2], two C-thioribonucleoside analogues of tiazofurin, are described. Direct trifluoroacetic acid-catalyzed C-glycosylation of ethyl furan-3-carboxylate with 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of α and β anomers. Ethyl 5-(2,3,5-tri-O-benzyl)-β-D-(4'-thioribofuranosyl)furan-3-carboxylate (6β) was debenzylated and then converted into the corresponding amide (furanthiofurin) by reaction with ammonium hydroxide. A similar C- glycosylation of ethyl thiophene-3-carboxylate with 1,2,3,5-tetra-O-acetyl-4- thio-D-ribofuranose catalyzed by stannic chloride afforded an anomeric mixture of 2- and 5-glycosylated regioisomers. Deacetylation of ethyl 5- (2,3,5-tri-O-acetyl)-β-D-(4'-thioribofuranosyl)thiophene-3-carboxylate (13β) with methanolic ammonia and treatment of the ethyl ester with ammonium hydroxide gave thiophenthiofurin. The glycosylation site and anomeric configuration were established by 1H NMR spectroscopy. Thiophenthiofurin was found to be cytotoxic in vitro toward human myelogenous leukemia K562, albeit 39-fold less than thiophenfurin, while furanthiofurin proved to be inactive. K562 cells incubated with thiophenthiofurin resulted in inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) and an increase in IMP pools with a concurrent decrease in GTP levels. From computational studies it was deduced that, among the C-nucleoside analogues of tiazofurin, activity requires an electrophilic sulfur adjacent to the C-glycosidic bond and an energetically favorable conformer around X = 0°. Among these, the more constrained (least flexible) compounds (tiazofurin and thiophenfurin) are more active than the less constrained thiophenthiofurin. Those compounds which contain a nucleophilic oxygen in place of the thiazole or thiophene (oxazofurin, furanfurin, and furanthiofurin) show the least activity.

Original languageEnglish (US)
Pages (from-to)1264-1270
Number of pages7
JournalJournal of Medicinal Chemistry
Volume43
Issue number7
DOIs
StatePublished - Apr 6 2000

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Franchetti, P., Marchetti, S., Cappellacci, L., Jayaram, H. N., Yalowitz, J. A., Goldstein, B. M., Barascut, J. L., Dukhan, D., Imbach, J. L., & Grifantini, M. (2000). Synthesis, conformational analysis, and biological activity of C- thioribonucleosides related to tiazofurin. Journal of Medicinal Chemistry, 43(7), 1264-1270. https://doi.org/10.1021/jm990257b