[structure: see text] An expedient, high-yielding synthesis of two types of triazole-linked glycopeptides is described. These novel and stable glycopeptide mimics were prepared via Cu(I)-catalyzed [3 + 2] cycloaddition of either azide-functionalized glycosides and acetylenic amino acids or acetylenic glycosides and azide-containing amino acids.

Arginine-glycine-aspartate (RGD) derivatives were prepared by a combination of solid-phase and solution-phase synthesis for selective targeting of alpha vbeta 3 integrin expressed in tumors. In order to evaluate the value of a triazole moiety as a proposed amide isostere, the side chain glycosylated cyclic RGD ( cRGD) peptides were synthesized with either a natural amide linkage or a triazole. Affinity of the cRGD constructs for the alpha vbeta 3 integrin was determined in a solid-phase competitive binding assay, showing strong similarity in binding affinity for each of the compounds under evaluation. Furthermore, the in vivo tumor targeting potential of glycosylated cRGD peptides, linked via amide or triazole, was investigated by determining the biodistribution of (125)I-labeled derivatives in mice with tumors expressing alpha vbeta 3. All of the cyclic RGD derivatives 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 present 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.

Endoglycosidase-catalyzed transglycosylation of triazole-linked glucose (Glc) and N-acetylglucosamine (GlcNAc)-containing dipeptides and polypeptides was achieved, using synthetic sugar oxazoline as the donor substrate. It was found that both N- and C-linked Glc/GlcNAc-containing triazole derivatives were effective substrates for endo-β-N-acetylglucosaminidase from Arthrobacter (Endo-A) for transglycosylation, demonstrating a broad acceptor substrate specificity for Endo-A. This chemoenzymatic method was successfully used for the synthesis of a novel triazole-linked C34 glycopeptide derived from HIV-1 envelope glycoprotein gp41. It was shown that the synthetic C34 glycopeptide possessed potent anti-HIV activity with an IC50 of 21 nM. The triazole-linked C34 glycopeptide demonstrated much enhanced stability toward protease- and glycoamidase-catalyzed digestion, showing the protective effects of glycosylation and the stability of the triazole linkage. These favorable properties suggest that the triazole-linked C34 glycopeptide may be valuable for further development as an anti-HIV drug candidate.

A synthesis route toward 2-deoxystreptamine, a common structure in many of the clinically important aminoglycosides, is presented. Starting from p-benzoquinone and cyclopentadiene, 2-deoxystreptamine is synthesized with key steps involving Pd(0)-catalyzed rearrangement, a retro-Diels-Alder by flash vacuum thermolysis, and Yb(III)-directed regioselective epoxide opening. The obtained diazidocyclitol 17 is a suitable 2-deoxystreptamine precursor, conveniently protected for incorporation in new aminoglycoside entities.

A copper-catalysed coupling of bromo-alkynes and organic azides is described. This coupling results in the formation of bromo-containing trisubstituted 1,2,3-triazole derivatives in high yield and a regioselective manner.