SYNTHESIS, STRUCTURE, AND ANTIPROLIFERATIVE ACTIVITY OF SELENOPHENFURIN, AN INOSINE 5'-MONOPHOSPHATE DEHYDROGENASE INHIBITOR ANALOG OF SELENAZOFURIN

The synthesis and biological activity of selenophenfurin (5-beta-D-rib ofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of s elenazofurin, are described. Glycosylation of ethyl selenophene-3-carb oxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5- glycosylated regioisomers, as a mixture of alpha- and beta-anomers, an d the beta-2,5-diglycosylated derivative. Deprotected ethyl 5-beta-D-r ibofuranosylselenophene-3-carboxylate (12 beta) was converted into sel enophenfurin by ammonolysis. The structure of 12 beta was determined b y H-1- and C-13-NMR, crystallographic, and computational studies. Sele nophenfurin proved to be antiproliferative against a number of leukemi a, lymphoma, and solid tumor cell lines at concentrations similar to t hose of selenazofurin but was more potent than the thiophene and thiaz ole analogues thiophenfurin and tiazofurin. Incubation of K562 cells w ith selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH ) (76%) and an increase in IMP pools (14.5-fold) with a concurrent dec rease in GTP levels (58%). The results obtained confirm the hypothesis that the presence of heteroatoms such as S or Se in the heterocycle i n position 2 with respect to the glycosidic bond is essential for both cytotoxicity and IMP dehydrogenase inhibitory activity in this type o f C-nucleosides.