Synthesis, Structure, and Antiproliferative Activity of Selenophenfurin, an Inosine 5‘-Monophosphate Dehydrogenase Inhibitor Analogue of Selenazofurin
- 1 May 1997
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (11) , 1731-1737
- https://doi.org/10.1021/jm960864o
Abstract
The synthesis and biological activity of selenophenfurin (5-beta-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 alpha- and beta-anomers, and the beta-2,5-diglycosylated derivative. Deprotected ethyl 5-beta-D-ribofuranosylselenophene-3-carboxylate (12 beta) was converted into selenophenfurin by ammonolysis. The structure of 12 beta 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.Keywords
This publication has 13 references indexed in Scilit:
- Assignment of Anomeric Configuration of D-Ribo-, Arabino-, 2′-Deoxyribo-, and 2′,3′-Dideoxyribonucleosides by Noe Difference SpectroscopyNucleosides, Nucleotides and Nucleic Acids, 1989
- Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compoundsJournal of Virological Methods, 1988
- Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agentAntimicrobial Agents and Chemotherapy, 1983
- Comparative invitro studies of tiazofurin and a selenazole analogBiochemical and Biophysical Research Communications, 1983
- Conversion of 2-β-D-ribofuranosylselenazole-4-carboxamide to an analogue of nad with potent imp dehydrogenase-inhibitory propertiesBiochemical Pharmacology, 1983
- A straightforward radiometric technique for measuring IMP dehydrogenaseAnalytical Biochemistry, 1983
- DNA binding studies of 7-bulky substituted actinomycin analogsJournal of Medicinal Chemistry, 1983
- Inhibition of inosinate dehydrogenase by metabolites of 2-β-D-ribofuranosylthiazole-4-car☐amideBiochemical and Biophysical Research Communications, 1982
- Partial purification, properties and regulation of inosine 5′-phosphate dehydrogenase in normal and malignant rat tissuesBiochemical Journal, 1977
- IMP dehydrogenase, an enzyme linked with proliferation and malignancyNature, 1975