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

Research output: Contribution to journalArticle

41 Citations (Scopus)

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

Fingerprint

tiazofurin
Thiophenes
Bioactivity
Glycosylation
Ammonium Hydroxide
IMP Dehydrogenase
Thiazoles
Trifluoroacetic Acid
Inosine Monophosphate
Guanosine Triphosphate
Myeloid Leukemia
Nucleosides
Ammonia
Sulfur
K562 Cells
Amides
Nuclear magnetic resonance spectroscopy
Esters
5-(4'-thioribofuranosyl)thiophene-3-carboxamide
Oxygen

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Franchetti, P., Marchetti, S., Cappellacci, L., Jayaram, H. N., Yalowitz, J. A., Goldstein, B. M., ... 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

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

In: Journal of Medicinal Chemistry, Vol. 43, No. 7, 06.04.2000, p. 1264-1270.

Research output: Contribution to journalArticle

Franchetti, P, Marchetti, S, Cappellacci, L, Jayaram, HN, Yalowitz, JA, Goldstein, BM, Barascut, JL, Dukhan, D, Imbach, JL & Grifantini, M 2000, 'Synthesis, conformational analysis, and biological activity of C- thioribonucleosides related to tiazofurin', Journal of Medicinal Chemistry, vol. 43, no. 7, pp. 1264-1270. https://doi.org/10.1021/jm990257b
Franchetti P, Marchetti S, Cappellacci L, Jayaram HN, Yalowitz JA, Goldstein BM et al. Synthesis, conformational analysis, and biological activity of C- thioribonucleosides related to tiazofurin. Journal of Medicinal Chemistry. 2000 Apr 6;43(7):1264-1270. https://doi.org/10.1021/jm990257b
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. / Synthesis, conformational analysis, and biological activity of C- thioribonucleosides related to tiazofurin. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 7. pp. 1264-1270.
@article{f271ab443a9a422782fa76aecac3956e,
title = "Synthesis, conformational analysis, and biological activity of C- thioribonucleosides related to tiazofurin",
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.",
author = "Palmarisa Franchetti and Stefano Marchetti and Loredana Cappellacci and Jayaram, {Hiremagalur N.} and Yalowitz, {Joel Aaron} and Goldstein, {Barry M.} and Barascut, {Jean Louis} and David Dukhan and Imbach, {Jean Louis} and Mario Grifantini",
year = "2000",
month = "4",
day = "6",
doi = "10.1021/jm990257b",
language = "English",
volume = "43",
pages = "1264--1270",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Synthesis, conformational analysis, and biological activity of C- thioribonucleosides related to tiazofurin

AU - Franchetti, Palmarisa

AU - Marchetti, Stefano

AU - Cappellacci, Loredana

AU - Jayaram, Hiremagalur N.

AU - Yalowitz, Joel Aaron

AU - Goldstein, Barry M.

AU - Barascut, Jean Louis

AU - Dukhan, David

AU - Imbach, Jean Louis

AU - Grifantini, Mario

PY - 2000/4/6

Y1 - 2000/4/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0034611616&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034611616&partnerID=8YFLogxK

U2 - 10.1021/jm990257b

DO - 10.1021/jm990257b

M3 - Article

VL - 43

SP - 1264

EP - 1270

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -