Synthesis, Conformational Analysis, and Biological Activity of C-Thioribonucleosides Related to Tiazofurin

• Published in: Journal of medicinal chemistry 2000-04, Vol.43 (7), p.1264-1270
• Main Authors: Franchetti, Palmarisa, Marchetti, Stefano, Cappellacci, Loredana, Jayaram, Hiremagalur N, Yalowitz, Joel Aaron, Goldstein, Barry M, Barascut, Jean-Louis, Dukhan, David, Imbach, Jean-Louis, Grifantini, Mario
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Drug Screening Assays, Antitumor; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; General aspects; Glycosylation; Humans; IMP Dehydrogenase - antagonists & inhibitors; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Ribavirin - analogs & derivatives; Ribavirin - chemical synthesis; Ribavirin - chemistry; Ribavirin - pharmacology; Ribonucleosides - chemistry; Ribose - analogs & derivatives; Ribose - chemical synthesis; Ribose - chemistry; Ribose - pharmacology; Structure-Activity Relationship; Thermodynamics; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990257b

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 χ = 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.