Toward Developing an Antimelanoma Topical Gel from Coordination Polymers Derived from a Nitrile-Functionalized Terpyridine Ligand and Dicarboxylic Acids

With the aim of developing a vehicle-free drug delivery (VFDD) system, a structural rationale has been exploited to synthesize a series of metallogelators derived from coordination polymers constituted with a nitrile-functionalized terpyridyl ligand (L), various dicarboxylic acids (2-amino terephthalate (2-NH₂TA), 2,6-naphthalene dicarboxylate (2,6-NDA), and 1,4-phenylene dicarboxylate (1,4-PDA)), and transition metal salts (Zn(NO₃)₂·6H₂O, Co(NO₃)₂·6H₂O, Ni(NO₃)₂·6H₂O). The coordination polymers (CP1-CP5), thus synthesized, were fully characterized by single-crystal X-ray diffraction (SXRD). Metallogels (CPG1-CPG5) were obtained by mixing stoichiometric amounts of the reactants of the coordination polymers in DMSO/water (3:2), as revealed by their single-crystal structures. The metallogels were characterized by dynamic rheology and electron microscopy. Biological studies revealed that the anticancer activity of the metallogelator CPG1 against the melanoma cell line (B16-F10) was superior to CPG2, with CPG1 being noncytotoxic to noncancerous cell lines (E. Derm and HEK 293) within the operating concentration range. CPG1 also showed appreciable ability to inhibit cell migration of B16-F10 cells in a scratch assay. Mechanistic studies indicated the involvement of apoptosis with cell cycle arrest in the G0/G1 phase. Side population discrimination assay showed that CPG1 could also kill the side population (SP) cells of B16-F10─a trait known to reduce the chance of metastasis. Intriguingly, CPG1 was also successful in preventing the growth of tumor spheroids derived from B16-F10 cells, highlighting its ability to prevent cancerous tumor growth. Thus, the corresponding metallogel CPG1 can further be developed as a topical gel for treating skin cancer-like scenarios because the B16-F10 cell line is often referred to as a human skin cancer model.