New Cu complexes containing methyl-phenanthroline and dipeptides as cytotoxic agents. Synthesis, characterization and in vitro studies

The high incidence and mortality associated with cancer evidence the need for novel therapeutic agents. Metal-based coordination compounds offer a diverse arsenal of molecules that can be developed into drugs, beyond those currently in clinical use. Among them, copper complexes are emerging as promising candidates for cancer treatment. In this study, a series of complexes [Cu(L-dipeptide)(met-phen)] (where met-phen: 4-methyl-1,10-phenanthroline and 5-methyl-1,10-phenanthroline) were synthesized and characterized. Solid-state characterization included the determination of the crystal structures of [Cu(Gly-Gly)(4met-phen)]·5.5 H₂O and [Cu(phe-ala)(4met-phen)]·3H₂O. DNA binding was assessed through the intrinsic binding constant (Kb) and relative viscosity measurements, indicating partial intercalation into calf-thymus DNA. The obtained Kb values were approximately tenfold lower than those reported for analogous complexes with phenanthroline. The cytotoxicity of the complexes was evaluated against a panel of human cancer cell lines: metastatic breast adenocarcinoma MDA-MB-231 (triple negative, ATCC: HTB-26), lung epithelial carcinoma A549 (ATCC: CCL-185), ovarian carcinoma A2780 (ECACC 93112519), and nontumoral lung cell line MRC-5 (ATCC: CCL-171). The complexes exhibited potent cytotoxicity, with IC₅₀ values in the low micromolar range, which was significantly more effective than that of cisplatin. [Cu(ala-gly)(5met-phen)] inhibits clonogenic colony formation and induces cellular death above its IC₅₀. These findings evidence that [Cu(L-dipeptide)(met-phen)] complexes are interesting candidates for further in vivo investigation.