Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin.
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.
Franchetti
P
P
Dipartimento di Scienze Chimiche, Università di Camerino, Italy. grima@camserv.unicam.it
Cappellacci
L
L
Sheikha
G A
GA
Jayaram
H N
HN
Gurudutt
V V
VV
Sint
T
T
Schneider
B P
BP
Jones
W D
WD
Goldstein
B M
BM
Perra
G
G
De Montis
A
A
Loi
A G
AG
La Colla
P
P
Grifantini
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007291:Inosine Monophosphate / Q000378:metabolism; D007938:Leukemia / Q000473:pathology; D008223:Lymphoma / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000473:pathology; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D012254:Ribavirin / Q000031:analogs & derivatives; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D012263:Ribonucleosides; C106280:selenophenfurin; D007291:Inosine Monophosphate; D012254:Ribavirin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C039064:selenazofurin