Synlett 2015; 26(19): 2663-2672
DOI: 10.1055/s-0035-1560591
letter
© Georg Thieme Verlag Stuttgart · New York

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

Nuno M. Xavier*a, Susana D. Lucasb, Radek Jordac, Stefan Schwarzd, Anne Loesched, René Csukd, M. Conceição Oliveirae
  • aCentro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 2º Piso, Campo Grande, 1749-016 Lisboa, Portugal   Email: nmxavier@fc.ul.pt
  • bInstituto de Investigação do Medicamento, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
  • cLaboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University & Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
  • dBereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle (Saale), Germany
  • eCentro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Further Information

Publication History

Received: 20 October 2015

Accepted after revision: 22 October 2015

Publication Date:
09 November 2015 (eFirst)

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.

Supporting Information