Synthesis of Novel Protected N_α(ω-Drug) Amino Acid Building Units for Facile Preparation of Anticancer Drug-Conjugates

Abstract: We report about the preparation of novel protected N_α(ω-drug) amino acid building units and their straightforward incorporation in solid phase synthesis for the preparation of peptide-drug conjugates. These building units were synthesized applying various coupling methods between anticancer drugs and the side chains of different N_α protected amino acids. Subsequent incorporation of these amino acid-drug motifs into linear and cyclic integrin RGD and NGR containing ligands enabled a non-linear/divergent synthetic pathway of medicinally potential peptide-drug conjugates. The synthetic routes reported in this work are both general and applicable, and significantly expand the scope of the conjugation capabilities for peptide drug conjugates. For the preliminary in vitro evaluation of the novel peptide-drug conjugates reported herein, selective cytotoxicity of two representatives—one linear and one cyclic RGD—camptothecin conjugates were evaluated on α_vβ₃ integrin overexpressed cancer cell lines. Graphical Abstract: [Figure not available: see fulltext.]