Furanfurin and Thiophenfurin: Two Novel Tiazofurin Analogs. Synthesis, Structure, Antitumor Activity, and Interactions with Inosine Monophosphate Dehydrogenase

Abstract

The syntheses of furan and thiophene analogues of tiazofurin (furanfurin and thiophenfurin, respectively) are described. Direct stannic chloride-catalyzed C-glycosylation of ethyl 3-furan-carboxylate (6) or ethyl 3-thiophencarboxylate (18) with 1,2,3,5-tetra-O-acetyl-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of alpha- and beta-anomers, and the beta-2,5-diglycosylated derivatives. Deprotection of ethyl 5-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)furan-3-carboxylate (9 beta) and ethyl 5-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)thiophene-3-carboxylate (20 beta) with sodium ethoxide afforded ethyl 5-beta-D-ribofuranosylfuran-3-carboxylate (12 beta) and ethyl 5-beta-D-ribofuranosylthiophene-3-carboxylate (23 beta) which were converted into 5-beta-D-ribofuranosylfuran-3-carboxamide (furanfurin, 4) and 5-beta-D-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 5) by reaction with ammonium hydroxide. The anomeric configuration and the site of glycosylation were established by 1H-NMR and proton-proton nuclear Overhauser effect difference spectroscopy. The structure of compound 23 beta was confirmed by X-ray crystallography. 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 resulted in inhibition of inosine monophosphate (IMP) dehydrogenase (63%) and an increase in IMP pools (6-fold) with a concurrent decrease in GTP levels (42%). Incubation of adenosine-labeled K562 cells with tiazofurin, thiophenfurin, and furanfurin resulted in a 2-fold higher NAD analogue formulation by thiophenfurin than by tiazofurin. Furanfurin was converted to the NAD analogue with only 10% efficiency. The results obtained support the hypothesis that the presence of S in the heterocycle in position 2 with respect to the glycosidic bond is essential for the cytotoxicity and IMP dehydrogenase activity of tiazofurin, while the N atom is not.

Novel nicotinamide adenine dinucleotide analogues as selective inhibitors of NAD+-dependent enzymes

“…8 When applied to carbonitrile thiophenes, this method failed to yield any C-glycosylation product. Attempts to introduce any other types of thiophenes, including the ethyl thiophene carboxylate employed by Franchetti and thiophene itself, either led to no product formation or polymerised unidentifiable material.…”

“…8 In his study, he observed that the S-atom remained cis to the furanose-oxygen and ab initio calculations suggested that this conformation was stabilised by an electrostatic interaction between a positively charged thiophene sulfur and a negatively charged furanose oxygen. Therefore, based on these observations, we could assume similar restricted rotation around the C-glycosidic bond of 7ab and 7bb.…”

“…Yet, in vivo, this derivative was found to be toxic. 8 Unspecific enzyme inhibition and metabolic modifications of thiophenfurin might be responsible for such an outcome.…”

A New Modular and Practical Methodology for the Synthesis of 4‐ or 3‐Substituted Phenyl C‐Nucleosides

“…Many of them possess antiviral or antineoplastic activities. [1] Quite recently, C-nucleosides bearing simple hydrophobic aryl and hetaryl groups as nucleobase surrogates attracted great attention due to their use in the extension of the genetic alphabet. [2] If incorporated to oligonucleotides, they selectively pair with the same of other hydrophobic nucleobase to form stable duplexes due to increased stacking and favourable desolvation energy as compared to canonical nucleobases.…”

Synthesis and antiviral studies of a novel isodideoxynucleoside: an analogue of the antiviral compound, tiazofurin

“…[3][4][5] In more recent studies, a series of isomeric dideoxynucleosides was synthesized in our laboratory. synthesized and studied the unusual isomeric C-dideoxynucleoside, 4(S)-(4-carbamoyl-thiazol-2-yl)-tetrahydro-2(S)-furan-methanol 4 and this paper describes the results of our synthesis and antiviral studies.…”