Dinuclear Platinum(II) Complexes Targeting DNA and Human Serum Albumin: Electrostatic Binding and Apoptosis-Driven Antiproliferative Activity.

Two novel dinuclear platinum(II) complexes, [{Pt(1,3-pnd)Cl}2(μ-4,4'-bipy)]Cl2 (Pt1) and [{Pt(1,3-pnd)Cl}2(μ-4,4'-SS-bipy)]Cl2 (Pt2), were synthesized and characterized by elemental analysis, UV-vis, and 1H/13C NMR spectroscopy. Spectroscopic and electrochemical studies showed that both complexes interact with CT-DNA predominantly through electrostatic association with the phosphate backbone. Fluorescence quenching confirmed static binding to HSA, while ibuprofen/warfarin displacement indicated binding outside Sudlow site II. Cytotoxicity assays demonstrated concentration-dependent antiproliferative effects in murine and human breast and colorectal cancer cells. Although Pt1 and Pt2 were generally less cytotoxic than established reference drugs, particularly cisplatin, Pt2 showed reduced toxicity toward noncancerous mMSCs. In CT26 cells, Pt2 induced apoptosis, increased Bax/Bcl-2 and Bax/Bcl-xL ratios, activated caspase-3, reduced Ki-67, altered cell-cycle distribution, increased p27 and p53, and suppressed AKT/mTOR signaling. These findings support further evaluation of Pt2 as a selective anticancer candidate with a mechanistic profile linking DNA interaction, apoptosis, checkpoint regulation, and impaired survival signaling within colorectal carcinoma cells.