FURANFURIN AND THIOPHENFURIN - 2 NOVEL TIAZOFURIN ANALOGS - SYNTHESIS, STRUCTURE, ANTITUMOR-ACTIVITY, AND INTERACTIONS WITH INOSINE MONOPHOSPHATE DEHYDROGENASE

The syntheses of furan and thiophene analogues of tiazofurin (furanfur in and thiophenfurin, respectively) are described. Direct stannic chlo ride-catalyzed C-glycosylation of ethyl 3-furancarboxylate (6) or ethy l 3-thiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-D-ribofuranos e gave 2- and 5-glycosylated regioisomers, as a mixture of alpha- and beta-anomers, and the beta-2,5-diglycosylated derivatives. Deprotectio n of ethyl -O-acetyl-beta-D-ribofuranosyl)furan-3-carboxylate (9 beta) and ethyl cetyl-beta-D-ribofuranosyl)thiophene-3-carboxylate (20 beta ) with sodium ethoxide afforded ethyl 5-beta-D-ribofuranosylfuran-3-ca rboxylate (12 beta) and ethyl 5-beta-D-ribofuranosylthiophene-3-carbox ylate (23 beta) which were converted into 5-beta-D-ribofuranosylfuran- 3-carboxamide (furanfurin, 4) and 5-beta-D-ribofuranosylthiophene-3-ca rboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by H-1-NMR and proton-proton nuclear Overhauser effect difference spec troscopy. The structure of compound 23 beta was confirmed by X-ray cry stallography. Thiophenfurin was found to be cytotoxic in vitro toward murine lymphocytic leukemia P388 and L1210, human myelogenous leukemia K562, human promyelocytic leukemia HL-60, human colon adenocarcinoma LoVo, and B16 melanoma at concentrations similar to that of tiazofurin . In the same test furanfurin proved to be inactive. Thiophenfurin was found active in vivo in BD2F1 mice inoculated with L1210 cells with a % T/C of 168 at 25 mg/kg. K562 cells incubation with thiophenfurin re sulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63% ) and an increase in IMP pools (g-fold) with a concurrent decrease in GTP levels (42%). Incubation of adenosine-labeled K562 cells with tiaz ofurin, thiophenfurin, and furanfurin resulted in a 2-fold higher NAD analogue formulation by thiophenfurin than by tiazofurin. Furanfurin w as converted to the NAD analogue with only 10% efficiency. The results obtained support the hypothesis that the presence of S in the heteroc ycle in position 2 with respect to the glycosidic bond is essential fo r the cytotoxicity and IMP dehydrogenase activity of tiazofurin, while the N atom is not.