Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin

Palmarisa Franchetti, Loredana Cappellacci, Ghassan Abu Sheikha, Hiremagalur N. Jayaram, Vivek V. Gurudutt, Thaw Sint, Bryan P. Schneider, William D. Jones, Barry M. Goldstein, Graziella Perra, Antonella De Montis, Anna Giulia Loi, Paolo La Colla, Mario Grifantini

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76 Scopus citations

Abstract

The synthesis and biological activity of selenophenfurin (5-β-D- ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of selenazofurin, are described. Glycosylation of ethyl selenophene-3- carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5- glycosylated regioisomers, as a mixture of α- and β-anomers, and the β- 2,5-diglycosylated derivative. Deprotected ethyl 5-β-D- ribofuranosylselenophene-3-carboxylate (12β) was converted into selenophenfurin by ammonolysis. The structure of 12β was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent decrease in GTP levels (58%). The results obtained confirm the hypothesis that the presence of heteroatoms such as S or Se in the heterocycle in position 2 with respect to the glycosidic bond is essential for both cytotoxicity and IMP dehydrogenase inhibitory activity in this type of C-nucleosides.

Original languageEnglish (US)
Pages (from-to)1731-1737
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number11
DOIs
StatePublished - May 23 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Franchetti, P., Cappellacci, L., Sheikha, G. A., Jayaram, H. N., Gurudutt, V. V., Sint, T., Schneider, B. P., Jones, W. D., Goldstein, B. M., Perra, G., De Montis, A., Loi, A. G., La Colla, P., & Grifantini, M. (1997). Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin. Journal of Medicinal Chemistry, 40(11), 1731-1737. https://doi.org/10.1021/jm960864o