Synthesis and Evaluation of the Biological Profile of Novel Analogues of Nucleosides and of Potential Mimetics of Sugar Phosphates and Nucleotides

Abstract

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 K i value of 11.9 μM. N-Glucuronylsulfonohydrazide showed good inhibition of CA-II (K i = 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.

Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

“…Most of the reported isonucleosides possess the nucleobase linked to furanose systems at C-2 or at C-3 [3,4,5,6,7,8,9,10,11], among which some molecules exhibited anticancer [4,5] or antiviral [6,7,8,9,11] activities. Pyranosyl isonucleosides have been relatively less exploited and the few reported examples include 2′-fluoroarabino-2′-yl pyrimidine derivatives [12], which displayed anticancer activities, and pyranos-6′-yl isonucleosides [13,14], which resulted from our previous investigations and showed selective and moderate to good inhibition of acetylcholinesterase (AChE). This enzyme hydrolyses the neurotransmitter acetylcholine and is a main therapeutic target for the symptomatic treatment of Alzheimer’s disease (AD) [15,16].…”

Anti-Tick-Borne Encephalitis Virus Activity of Novel Uridine Glycoconjugates Containing Amide or/and 1,2,3-Triazole Moiety in the Linker Structure

“…There are also reports of the synthesis of a (triazolyl) methyl amide-linked disaccharide nucleosides as analogues of nucleoside diphosphate sugars. Some of the obtained 6′-isonucleosides and triazole-containing glycoderivatives displayed acetylcholinesterase inhibitory activities [ 25 ]. Nucleoside triphosphate mimetic, where the phosphate residues-containing chain was replaced by an uncharged methylene-triazole moiety, are also known to have occurred.…”

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

“…Few examples of guanidine-containing molecules exhibiting cholinesterase inhibitory ability were reported [16,17,44]. Moreover, we have previously found the inhibitory effects of aminopurine and guanine isonucleosides on the activity of acetylcholinesterase [45,46], which further motivated us to evaluate the anticholinesterasic activities of simpler guanidine-containing sugar derivatives such as the synthesized 5-guanidino furanoses. All compounds were assessed for their antiproliferative effects on cancer cells.…”