Efficient synthesis of exomethylene- and keto-exomethylene-d-glucopyranosyl nucleoside analogs as potential cytotoxic agents

Abstract

A novel series of exomethylene- and keto-exomethylene-d-glucopyranonucleosides with thymine, uracil, and 5-fluorouracil as heterocyclic bases have been designed and synthesized. Wittig condensation of the 3-keto glucoside 1 gave the corresponding 1,2:5,6-di-O-isopropylidene-3-deoxy-3-methylene-d-glucofuranose (2), which after hydrolysis and acetylation led to the precursor 1,2,4,6-tetra-O-acetyl-3-deoxy-3-methylene-d-glucopyranose (4). Compound 4 was condensed with silylated thymine, uracil, and 5-fluorouracil, respectively, deacetylated and acetalated to afford 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl)pyrimidines 7a-c. Oxidation of the free hydroxyl group in the 2'-position of the sugar moiety led to the formation of the labile 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl-2'-ulose)pyrimidines 8a-c. Finally, deisopropylidenation of the resulted derivatives 8a-c afforded the diol nucleosides 9a-c. The target keto-exomethylene analogs 9a-c were more cytostatic against a variety of tumor cell lines than the corresponding saturated-hydroxy-exomethylene derivatives 6. In particular, the 5-fluorouracil derivative 9c was highly cytostatic at an IC(50) (50% inhibitory concentration) ranging between 0.56 and 9.4 microg/mL, which was comparable to the free parental 5-fluorouracil base.

Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions

“…Our investigation was continued with the hydrothiolation of the pyranosyl C3-exomethylene 33 (Scheme 5). The deprotection of glucofuranosyl 3-exomethylene 32 [44] while using TFA, followed by Ac2O-NaOAc mediated acetylation furnished the pyranose derivative 33 [45] in β-anomeric form. The hydrothiolation of 33 with thiols 2a and 2e occurred with full stereoselectivity and high yields The methyl α-D-galactopyranoside derivative 22 with a C2 exocyclic double bond was also synthesized, starting from compound 20, in order to study the effect of the enose configuration on the stereochemical outcome of the hydrothiolation reaction [41] (Scheme 3).…”

“…Our investigation was continued with the hydrothiolation of the pyranosyl C3-exomethylene 33 (Scheme 5). The deprotection of glucofuranosyl 3-exomethylene 32 [44] while using TFA, followed by Ac 2 O-NaOAc mediated acetylation furnished the pyranose derivative 33 [45] in β-anomeric form. The hydrothiolation of 33 with thiols 2a and 2e occurred with full stereoselectivity and high yields producing the thiodisaccharides 34 and 35 with an equtorial carbon-sulfur linkage at position C3.…”