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 Schneider, William D. Jones, Barry M. Goldstein, Graziella Perra, Antonella De Montis, Anna Giulia Loi, Paolo La Colla, Mario Grifantini

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

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IMP Dehydrogenase
tiazofurin
Glycosylation
Thiazoles
Thiophenes
Inosine Monophosphate
K562 Cells
Cytotoxicity
Guanosine Triphosphate
Bioactivity
Tumor Cell Line
Nucleosides
Tumors
Lymphoma
Leukemia
Cells
Nuclear magnetic resonance
Derivatives
selenophenfurin
selenazofurin

ASJC Scopus subject areas

  • Organic Chemistry

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Franchetti, P., Cappellacci, L., Sheikha, G. A., Jayaram, H. N., Gurudutt, V. V., Sint, T., ... 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

Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin. / Franchetti, Palmarisa; Cappellacci, Loredana; Sheikha, Ghassan Abu; Jayaram, Hiremagalur N.; Gurudutt, Vivek V.; Sint, Thaw; Schneider, Bryan; Jones, William D.; Goldstein, Barry M.; Perra, Graziella; De Montis, Antonella; Loi, Anna Giulia; La Colla, Paolo; Grifantini, Mario.

In: Journal of Medicinal Chemistry, Vol. 40, No. 11, 23.05.1997, p. 1731-1737.

Research output: Contribution to journalArticle

Franchetti, P, Cappellacci, L, Sheikha, GA, Jayaram, HN, Gurudutt, VV, Sint, T, Schneider, B, Jones, WD, Goldstein, BM, Perra, G, De Montis, A, Loi, AG, 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, vol. 40, no. 11, pp. 1731-1737. https://doi.org/10.1021/jm960864o
Franchetti, Palmarisa ; Cappellacci, Loredana ; Sheikha, Ghassan Abu ; Jayaram, Hiremagalur N. ; Gurudutt, Vivek V. ; Sint, Thaw ; Schneider, Bryan ; Jones, William D. ; Goldstein, Barry M. ; Perra, Graziella ; De Montis, Antonella ; Loi, Anna Giulia ; La Colla, Paolo ; Grifantini, Mario. / Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 11. pp. 1731-1737.
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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.",
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T1 - Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin

AU - Franchetti, Palmarisa

AU - Cappellacci, Loredana

AU - Sheikha, Ghassan Abu

AU - Jayaram, Hiremagalur N.

AU - Gurudutt, Vivek V.

AU - Sint, Thaw

AU - Schneider, Bryan

AU - Jones, William D.

AU - Goldstein, Barry M.

AU - Perra, Graziella

AU - De Montis, Antonella

AU - Loi, Anna Giulia

AU - La Colla, Paolo

AU - Grifantini, Mario

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N2 - 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.

AB - 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.

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