Anticancer Structure–Activity Relationship in Well-Characterized Pt (IV) Compounds: Pt (CH3) 2I26, 6′-dimethyl-2, 2′-bipyridine Cytotoxicity Against Colon and Ovarian Carcinoma Cell Lines

Well-defined, small-molecule, platinum-centered coordination compounds are of continued interest in both basic and applied research, particularly in medicinal chemistry and pharmaceuticals (i. e. , cisplatin). Organoplatinum (IV) complexes have been reported to exhibit substantial in vitro cytotoxicity across a range of cancer cell lines. Compared with coordinatively unsaturated platinum (II) species, electronically and coordinatively saturated platinum (IV) complexes are generally more inert, reducing undesirable side reactions in plasma and cellular environments and potentially improving their safety profiles as chemotherapeutic agents. In addition, the presence of organic ligands can enhance lipophilicity, facilitating passive diffusion across cell membranes. Here, we report the synthesis, structural characterization, and in vitro anticancer activity of a series of organoplatinum (IV) complexes of the general formula Pt (CH3) 2I2n, n′-dimethyl-2, 2′-bipyridine (n, n′ = 4, 4′; 5, 5′; 6, 6′). The 5, 5′- and 6, 6′-dimethyl isomers were characterized by single-crystal X-ray diffraction. All three dimethyl-substituted complexes, along with the parent compound, Pt (CH3) 2I22, 2′-bipyridine, were evaluated for cytotoxic activity against a panel of 60 human cancer cell lines. Whereas Pt (CH3) 2I22, 2′-bipyridine and the 4, 4′- and 5, 5′-dimethyl derivatives displayed limited cytotoxicity, the 6, 6′-dimethyl isomer exhibited notable activity, particularly against the colon cancer cell line HCT-116 (LC50 = 8. 17 μM) and the ovarian cancer cell line OVCAR-3 (LC50 = 7. 34 μM). The enhanced cytotoxicity of the 6, 6′-dimethyl derivative is attributed, at least in part, to the relatively facile dissociation of the 6, 6′-dimethyl-2, 2′-bipyridine ligand from the platinum (IV) center, suggesting that sterically induced ligand lability plays an important role in modulating biological activity in this particular compound, giving new structural activity impetus for potential drug molecules.