Ligand substitution versus DNA-binding affinity : ǂb syntheses, structures, and in vitro anticancer activities of Pt(CH₃)₂I₂{2,2'-bipy-n,n'-(CH₃)₂} (n,n' = 4,4'; 5,5'; 6,6')

Abstract

In chemotherapeutic treatment for leukemia, the drug cisplatin is highly effective. However, there is an immense need for cisplatin analogues that are more clinically viable. Cancer cell assay studies have shown that the platinum(IV) complex Pt(CH₃)₂I₂{2,2'-bipyridine} exhibits significant anticancer activity against the human breast cancer cell line ZR-75-1, with an EC50 (effective concentration 50%) concentration of 6.1 μM— substantially lower than that of cisplatin (16.4 μM). To explore the unknown structure-activity relationship between DNA binding and anti-cancer activity, three isomers — Pt(CH₃)₂I₂{2,2'-bipy-n,n'-(CH₃)₂} where n,n’ = 4,4’; 5,5’; 6,6’— were synthesized. The intent was to demonstrate decreased cytotoxicity as complex-DNA steric hindrance increased through the positioning of the methyl groups on the bipyridine ring of the isomers. All isomers were structurally characterized via single-crystal X-ray diffraction, nuclear magnetic resonance (NMR), and infrared spectroscopy (IR). Their cytotoxic profiles were evaluated through the National Cancer Institute’s Sulforhodamine B screening assay. Among them, Pt(CH₃)₂I₂{2,2'-bipy-6,6'-(CH₃)₂} demonstrated the most potent activity with a notable LC50 (lethal concentration 50% ) value of 7.34 μM against ovarian cancer (OVCAR-3). DNA- binding studies using UV-Vis absorption spectroscopy revealed intrinsic binding constants (Kb) of 1.74×10⁴ M⁻¹ and 3.74×10⁴ M⁻¹ for the 6,6'-dimethyl and unsubstituted bipyridine complexes, respectively. A competitive displacement reaction monitored by 'H NMR showed that Pt(CH₃)₂I₂{2,2'-bipy-6,6'-(CH₃)₂} reacts completely with free 2,2’-bipyridine to yield Pt(CH₃)₂I₂{2,2'-bipyridine} and liberated 6,6’-dimethyl bipyridine. These findings suggest that DNA-binding affinity does not directly correlate with cytotoxic potential and that steric factors introduced by ligand substitution play a more critical role in determining anticancer efficacy in these bipyridine-stabilized platinum(IV) compounds.