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The synthesis and anticancer evaluation of new series of nucleosides constructed on 5/6-azidoglycosyl or glucuronamide moieties and containing an O- or an N-dodecyl chain, respectively, are disclosed. Based on our previous results, their structures were planned to preclude them to act via a similar metabolic pathway than that of clinically used nucleoside antimetabolites, against which cancer cells frequently acquire resistance. Xylo and gluco-configured 5/6-azido-1,2-di-O-acetyl furanosyl and pyranosyl donors containing a 3-O-dodecyl group were synthesized from diacetone-d-glucose and were subsequently coupled with silylated uracil or 2-acetamido-6-chloropurine. N-Dodecyl glucuronamide-based nucleosides were accessed from acetonide-protected glucofuranurono-6,3-lactone, which was converted in few steps into O-benzylated 1,2-di-O-acetyl furanuronamide or pyranuronamide derivatives to undergo further N-glycosylation. Both types of nucleosides demonstrated notorious antiproliferative effects in chronic myeloid leukemia (K562) and in breast cancer (MCF-7) cells. The most potent molecules were a 6ʹ-azidoglucopyranosyl N7-linked purine nucleoside and glucofuranuronamide derivatives comprising N1-linked uracil and N7-linked purine units with activities in the single-digit micromolar order of concentration against both cell lines. Their GI50 values in MCF-7 cells were similar or ca. 3-fold lower than that of the standard drug 5-fluorouracil. Cell cycle studies and immunoblotting analysis of apoptosis-associated proteins in treated K562 cells indicated that the antiproliferative effect of the most effective nucleosides is based on apoptosis induction. [ABSTRACT FROM AUTHOR]

Eleven ruthenium-nucleoside conjugates with the general formula [(η5-C5H5)Ru(PP)L][PF6] (PP = 1,2-bis(diphenylphosphino)ethane (Dppe), 2PPh3, and L = 3-N-(p-cyanobenzyl)thymidine derivative ligand) are reported. Both [(η5-C5H5)Ru(Dppe)N≡C-R]+ and [(η5-C5H5)Ru(PPh3)2N≡C-R]+ scaffolds exhibit remarkable stability towards hydrolysis. Compounds show high cytotoxicity in HCT116 colon cancer cells, with IC50 values down to 1.0 μM. Uptake competition experiments with 2′-deoxyadenosine revealed its cellular absorption to be independent of nucleoside transporters. [ABSTRACT FROM AUTHOR]

The synthesis of novel types of furanosyl nucleoside analogues, namely N‐(benzyltriazolyl)methyl glucuronamide derivatives, N‐dodecyl glucuronamide‐based phenyltriazole nucleosides, and theobromine xylosyl 5′‐isonucleosides, as potential cholinesterase inhibitors is described herein. O‐Substituted and partially O‐substituted N‐propargyl glucuronamides, accessed from glucofuranurono‐6,3‐lactone, were engaged in CuI‐catalyzed cycloaddition with benzyl azide, whereas their N‐dodecyl uronamide counterparts were converted in three steps into glycosyl azides, which were subjected to cycloaddition with phenylacetylene. A xylofuranose derivative having a free 5‐OH group was coupled with theobromine by Mitsunobu reaction and the obtained isonucleoside was functionalized at C‐1′ with a sulfonamide moiety, leading to a prospective nucleotide mimetic. Five compounds displayed selective inhibition of acetylcholinesterase in the micromolar concentration range, with an α‐glycosyl triazole (Ki = 3.53 µm) and its 1‐azido‐uronamide precursor (Ki = 1.73 µm) being the most active. Docking studies were performed to give insights into the different inhibitory behavior within glycosyl azide anomers. Two of the best inhibitors showed low toxicity in both a neural cell line and human fibroblasts, rendering them promising lead compounds and supporting further investigations. [ABSTRACT FROM AUTHOR]

New xylofuranosyl and glucopyranosyl nucleoside phosphoramidates were synthesized as potential mimetics of nucleoside 5′-monophosphates. Their access involved N-glycosylation of uracil and 2-acetamido-6-chloropurine with 5′/6′-azido-1,2-di-O-acetyl glycosyl donors and subsequent Staudinger-phosphite reaction of the resulting azido nucleosides. The coupling of the purine derivative with the pyranosyl donor furnished N9 and N7-linked nucleosides in 1:1 ratio, whereas with the furanosyl donor, the N9-nucleoside was the major regioisomer formed. When using uracil, only 5′/6′-azido N1-linked nucleosides were obtained. The purine 5′/6′-azido nucleosides were converted into corresponding phosphoramidates in good yields. The antiproliferative effects of the nucleoside phosphoramidates and those of the azido counterparts on cancer cells were evaluated. While the nucleoside phosphoramidates did not show significant activities, the purine 5′/6′-azido nucleosides displayed potent effects against K562, MCF-7 and BT474 cell lines. The 5′-azidofuranosyl N9 and N7-linked purine nucleosides exhibited highest activity towards the chronic myeloid leukemia cell line (K562) with GI50 values of 13.6 and 9.7 μM, respectively. Among pyranosyl nucleosides, the N7-linked nucleoside was the most active compound with efficacy towards all cell lines assayed and a highest effect on K562 cells (GI50=6.8 μM). Cell cycle analysis of K562 and MCF-7 cells showed that the most active compounds cause G2/M arrest. [ABSTRACT FROM AUTHOR]

The synthesis of purine/triazole 6'-isonucleosides and of glucuronic acid/glucuronamide-derived N-glycosylsulfonohydrazides through efficient and stereo- or regioselective methodologies is described. Their structures were envisaged to mimic nucleosides, sugar phosphates, or nucleotides, and were expected to provide potential inhibitors of therapeutically relevant enzymes, the active sites of which could potentially bind their structural fragments or functional groups. Such enzymes include cholinesterases, carbonic anhydrase II (CA-II) and cyclin-dependent kinase 2 (CDK-2). A (triazolyl)methyl amide-linked disaccharide nucleoside, based on a new prospective structural framework for analogues of nucleoside diphosphate sugars, was synthesized. The synthetic strategies employed unprotected or partially protected carbohydrate derivatives as precursors, including ribose, glucuronic acid, glucuronolactone, and glycopyranosides and relied on stereoselective N-glycosylation, regioselective Mitsunobu coupling and 'click chemistry' approaches. Some 6'-isonucleosides and triazole-containing glycoderivatives displayed moderate selective acetylcholinesterase inhibitory activities. The best inhibitor was an aminomethyltriazole 6'-isonucleoside with a Ki value of 11.9 μM. N-Glucuronylsulfonohydrazide showed good inhibition of CA-II (Ki = 9.5 μM). Molecular docking of the most active compounds into the effected enzymes showed interactions with key amino acid residues for substrate recognition. In addition, the tested compounds did not show toxicity to normal cells. [ABSTRACT FROM AUTHOR]