Triazole-linked glycosyl amino acids and peptides : synthesis

Abstract

Naturally occurring glycosylated peptides play an important role in various biological processes and are therefore interesting lead molecules for the preparation of new therapeutic drugs.Synthesis of these natural glycopeptides is frequently hampered by the sensitivity of the natural glycosidic linkage towards enzymatic cleavage of the carbohydrate moiety. Herein we describe our efforts to prepare stable glycosidic C-linked serine isosteres by ligation of an open-chain unsaturated sugar to an allylglycine derivative, producing acyclic glycoamino acid alkenes as wel as a a novel, expedient, high-yielding synthesis of triazole-linked glycopeptides via Cu(I)catalyzed [3+2] cycloaddition of azidofunctionalized glycosides and acetylenic amino acids. The latter triazole-linked products, mimicking the N-linked glycosides found in Nature, have potentially relevant biological properties. Moreover, a range of protective groups were examined for application in an orthogonal coupling procedure en route to triazole analogues of natural glycopeptides with multiple glycosylated side-chains. The triazole-linked glycosidic amino acids are compatible with both solution as well as solid-phase peptide synthesis. In addition, the chemoenzymatic peptide coupling of glycosylated triazolyl- and amide-linked amino acid methyl esters, effected by alcalase, is described. Preparation of several cyclic RGD derivatives for selective targeting of avß3 integrin expressed in tumors and subsequent in vivo testing showed preferential uptake in the subcutaneous tumors, with the highest tumor-to-blood ratio measured for the triazole-linked glycosylated derivative. The results of the study are a clear indication of the value of the triazole moiety as a suitable amide isostere in the development of glycosylated peptides as pharmaceuticals. In addition, a novel copper-catalyzed cycloaddition of bromoalkynes and organic azides is described. Copper-mediated coupling resulted in the formation of bromo-containing trisubstituted [1,2,3]-triazole derivatives in high yield and a regioselective manner, and was applied in the cycloaddition of a variety of bromoacetylenes and azides