Synthesis of novel -acyl--d-glucopyranosylamines and ureas as potential lead cytostatic agents.

Novel classes of acetylated and fully deprotected -acyl--d-glucopyranosylamines and ureas have been synthesized and biologically evaluated. Acylation of the per--acetylated -d-glucopyranosylurea (), easily prepared via its corresponding phosphinimine derivative, by zinc chloride catalyzed reaction of the corresponding acyl chlorides RCOCl (-) gave the protected -acyl--d-glucopyranosylureas (-), in acceptable-to-moderate yields. Subsequent deacetylation of analogues - under Zemplén conditions afforded the fully deprotected derivatives , while the desired urea was formed after treatment of with dibutyltin oxide.

An easy microwave-assisted synthesis of C8-alkynyl adenine pyranonucleosides as novel cytotoxic antitumor agents.

We describe the synthesis of C8-alkynyl adenine pyranonucleosides 4, 5, and 8-phenylethynyl-adenine (II), via Sonogashira cross-coupling reaction under microwave irradiation. Compounds 4e and II were less cytostatic than 5-fluorouracil (almost an order of magnitude) against murine leukemia (L1210) and human cervix carcinoma (HeLa) cells, while the same compounds proved to be more active than 5-fluorouracil against human lymphocyte (CEM) cells.

Branched-chain sugar nucleosides: stereocontrolled synthesis and bioevaluation of novel 3'-C-trifluoromethyl and 3'-C-methyl pyranonucleosides.

A new series of 3'-C-trifluoromethyl- and 3'-C-methyl-β-d-allopyranonucleosides of 5-fluorouracil and their deoxy derivatives has been designed and synthesized. Treatment of ketosugar 1 with trifluoromethyltrimethylsilane under catalytic fluoride activation and methyl magnesium bromide, gave 1,2:5,6-di-O-isopropylidene-3-C-trifluoromethyl (2a) and 3-C-methyl (2b)-α-D-allofuranose, respectively, in a virtually quantitative yield and with complete stereoselectivity. Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-trifluoromethyl (3a) and 3-C-methyl (3b)-β-D-allopyranose.

Synthesis of novel thiopurine pyranonucleosides: evaluation of their bioactivity.

We report the synthesis of novel thiopurine pyranonucleosides. Direct coupling of silylated 6-mercaptopurine and 6-thioguanine with the appropriate pyranoses 1a-e via Vorbrüggen nucleosidation, gave the N-9 linked mercaptopurine 2a-e and thioguanine 4a-e nucleosides, while their N-7 substituted congeners 10a-e and 7a-e, were obtained through condensation of the same acetates with 6-chloro and 2-amino-6-chloropurines, followed by subsequent thionation. Nucleosides 3a-e, 5a-e, 8a-e, and 11a-e were evaluated for their cytostatic activity in three different tumor cell proliferative assays.

Stereoselective facile synthesis of 2'-spiro pyrimidine pyranonucleosides via their key intermediate 2'-C-cyano analogues. Evaluation of their bioactivity.

A novel series of 2'-spiro pyrimidine pyranonucleosides has been designed and synthesized. Their precursors, 2'-C-cyano nucleosides 5a,b and 6a,b, were obtained by subjecting 1a,b to the sequence of selective protection of the primary hydroxyl group, acetalation, oxidation, and finally treatment with sodium cyanide. Deoxygenation at the 2'-position of cyanohydrins 5a,b or 6a,b led to the 2'-deoxy derivatives 9a,b.

Rapid microwave-enhanced synthesis of C5-alkynyl pyranonucleosides as novel cytotoxic antitumor agents.

A microwave-assisted, one-pot, coupling reaction for the synthesis of C5-alkynyl-uracil and cytosine glucopyranonucleosides has been developed. The reaction is carried out under standard Sonogashira coupling conditions from glucopyranonucleosides of 5-iodouracil or 5-iodocytosine and various terminal alkynes. All compounds were evaluated for their cytostatic and antiviral activity.

Stereocontrolled synthesis of 4'-C-cyano and 4'-C-cyano-4'-deoxy pyrimidine pyranonucleosides as potential chemotherapeutic agents.

A new series of 4'-C-cyano and 4'-C-cyano-4'-deoxy pyrimidine pyranonucleosides has been designed and synthesized. Commercially available 1,2,3,4,6-penta-O-acetyl-D-mannopyranose (1) was condensed with silylated 5-fluorouracil, uracil, and thymine, respectively to afford after deacetylation 1-(α-D-mannopyranosyl)nucleosides (2a-c). Subjecting 2a-c to the sequence of specific acetalation, selective protection of the primary hydroxyl group and oxidation, the 4'-ketonucleosides 6a-c and 7c were obtained.

Stereocontrolled facile synthesis and biological evaluation of (3'S) and (3'R)-3'-amino (and Azido)-3'-deoxy pyranonucleosides.

This article describes the synthesis of (3 'S) and (3 'R)-3 '-amino-3 '-deoxy pyranonucleosides and their precursors (3 'S) and (3 'R)-3 '-azido-3 '-deoxy pyranonucleosides. Azidation of 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-D-allofuranose followed by hydrolysis and subsequent acetylation afforded 3-azido-3-deoxy-1,2,4,6-tetra-O-acetyl-D-glucopyranose, which upon coupling with the proper silylated bases, deacetylation, and catalytic hydrogenation, obtained the target 3 '-amino-3 '-deoxy-β-D-glucopyranonucleosides. The desired 1-(3 '-amino-3 '-deoxy-β-D-allopyranosyl)5-fluorouracil was readily prepared from the suitable imidazylate sugar after azidation followed by a protection/deprotection sequence and reduction of the unprotected azido precursor.

The σ-hole phenomenon of halogen atoms forms the structural basis of the strong inhibitory potency of C5 halogen substituted glucopyranosyl nucleosides towards glycogen phosphorylase b.

C5 halogen substituted glucopyranosyl nucleosides (1-(β-D-glucopyranosyl)-5-X-uracil; X=Cl, Br, I) have been discovered as some of the most potent active site inhibitors of glycogen phosphorylase (GP), with respective K(i) values of 1.02, 3.27, and 1.