Synthesis, Structure, and Antiproliferative Activity of Selenophenfurin, an Inosine 5‘-Monophosphate Dehydrogenase Inhibitor Analogue of Selenazofurin

• Published in: Journal of medicinal chemistry Vol. 40; no. 11; pp. 1731 - 1737
• Main Authors: Franchetti, Palmarisa, Cappellacci, Loredana, Sheikha, Ghassan Abu, Jayaram, Hiremagalur N, Gurudutt, Vivek V, Sint, Thaw, Schneider, Bryan P, Jones, William D, Goldstein, Barry M, Perra, Graziella, De Montis, Antonella, Loi, Anna Giulia, La Colla, Paolo, Grifantini, Mario
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.05.1997; Amer Chemical Soc
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Chemistry, Medicinal; Computer Simulation; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; General aspects; Guanosine Triphosphate - metabolism; Humans; IMP Dehydrogenase - antagonists & inhibitors; Inosine Monophosphate - metabolism; Leukemia - pathology; Life Sciences & Biomedicine; Lymphoma - pathology; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Models, Molecular; Molecular Structure; Neoplasms - pathology; Organoselenium Compounds - chemical synthesis; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Ribonucleosides - chemical synthesis; Ribonucleosides - chemistry; Ribonucleosides - pharmacology; Science & Technology; Tumor Cells, Cultured; AGENT; HUMAN NORMAL LYMPHOCYTES; 2-BETA-D-RIBOFURANOSYLSELENAZOLE-4-CARBOXAMIDE; 2-BETA-D-RIBOFURANOSYLTHIAZOLE-4-CARBOXAMIDE; MECHANISM; PROLIFERATION; HUMAN IMP DEHYDROGENASE; TIAZOFURIN; EXPRESSION; Antineoplastic agent; Human; Cell proliferation; Solid tumor; C-Nucleoside; Five membered ring; Molecular structure; Enzyme; Ab initio method; Selenium heterocycle; IMP dehydrogenase; Enzyme inhibitor; Malignant tumor; In vitro; Biological activity; Established cell line; Carboxamide; Oxidoreductases; Inhibition; Chemical synthesis; Tumor cell; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960864o

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.