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

• Two cyclic peptide-dasatinib conjugates were synthesized with Cathepsin B-sensitive linkers. • Utilized succinate and glutarate linkers to reduce steric hindrance. • Solid-phase peptide synthesis and solution-phase cyclization were employed for conjugate assembly. • The conjugates demonstrated IC 50 values of 4.2 μM and 8.8 μM against human melanoma A375 cells. 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 IC 50 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.