Preparation and Evaluation of Glycosylated Arginine–Glycine–Aspartate (RGD) Derivatives for Integrin Targeting

Abstract

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.

Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

“…To a solution of glycoside 27 (106 mg, 0.12 mmol) and Fmocprotected L-propargylglycine (41 mg, 0.12 mmol) 22 in tertbutanol (2 mL) and water (4 ml) was added a solution of CuSO 4 (0.04 M, 0.6 mL, 0.024 mmol) and sodium ascorbate (0.08 M, 0.6 mL) in H 2 O. The mixture was stirred overnight, water (6 mL) was added, and the product was extracted with CH 2 Cl 2 (2 × 25 mL).…”

Highly efficient click labeling using 2-[18F]fluoroethyl azide and synthesis of an 18FN-hydroxysuccinimide ester as conjugation agent

“…The 1,2,3-triazole group is stable to acid and basic hydrolysis, as well as reductive and oxidative conditions due to its aromaticity. Furthermore, this triazole group is biologically stable [10] and possesses a polarity and size similar to that of an amide bond [11], thereby improving water solubility [12] and allowing the synthesis of a wide-range of compounds with biological potential [13]. Because of these features of the click reaction and the readily accessible building blocks with azide and alkyne, click labeling has become a valuable and powerful tool in PET chemistry [9].…”

Recent Developments in Neoglycopeptide Synthesis

“…After establishing syntheses of neoglycosides by CuAAC, Rutjes et al [98] reported the synthesis of glycosylated cyclic arginine-glycine-aspartate (RGD) derivatives with either a natural amide bond or a triazole linker for selective targeting of a v b 3 integrin. Solid-phase binding assays revealed no significant difference in binding affinity and biodistribution studies suggested improved pharmacological properties of the triazole-linked compounds [98]. In a subsequent account, Rutjes et al [99] synthesized several new triazole-linked glycosides from protected and unprotected glycosyl donors with propargylglycine and azidoalanine derivatives.…”