Synthesis and evaluation of cyclic peptide-dasatinib conjugates as anti-melanoma agents

Abstract

Herein, we synthesized two amphiphilic cyclic peptides, incorporating tryptophan and arginine residues, linked to dasatinib via a Cathepsin B-sensitive tetrapeptide (Gly-Phe-Leu-Gly). To mitigate steric hindrance and optimize drug release, we integrated two different linkers, succinate and glutarate, between the drug and peptide. The synthesis involved solid-phase techniques for the assembly of the peptide, followed by the coupling of the peptide on-resin with the linker, mild cleavage, and solution-phase cyclization. Conjugation of the peptide-attached linker with dasatinib was conducted in the presence of N-methylmorpholine and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), generating the novel prodrugs. The synthesized compounds were characterized by high-resolution mass spectrometry MALDI, and the purity was confirmed by analytical HPLC. The synthesized cyclic peptide-dasatinib conjugates containing glutarate and succinate linkers were further evaluated against human melanoma A375 cells, which exhibited IC₅₀ values of 4.2 μM and 8.8 μM, respectively. Variations in cytotoxicity could be attributed to linker properties affecting intracellular drug release or prodrug uptake.