Differences in Stability, Cytotoxicity, and Mechanism of Action of Ru(II) and Pt(II) Complexes of a Bidentate N,O Donor Ligand

Abstract

We report [Ru-II(L)(eta(6)-p-cym)Cl] (1 and 2) and [Pt-II(L)(DMSO)Cl] (3 and 4) complexes, where L is a chelate imine ligand derived from chloroethylamine and salicylaldehyde (HL1) or o-vanillin (HL2). The complexes were characterized by single-crystal X-ray diffraction and other analytical techniques. The H-1 nuclear magnetic resonance data show that both the Ru(II) and Pt(II) complexes start forming the aquated complex within an hour. The aquated complexes are stable at least up to 24 h. The complexes bind to the N-7 of the model nucleobase 9-ethylguanine (9-EtG). Interaction with calf thymus (CT) DNA shows moderate binding interactions with binding constants, K-b (3.7 +/- 1.2) x 10(3) M-1 and (4.3 +/- 1.9) x 10(3) M-1 for 1 and 3, respectively. The complexes exhibit significant antiproliferative activity against human pancreas ductal adenocarcinoma (Mia PaCa-2), triple negative metastatic breast adenocarcinoma (MDA-MB-231), hepatocellular carcinoma (Hep G2), and colorectal adenocarcinoma (HT-29) cell lines. The studies show that with the same ligand the Pt(II) complexes are more potent than the Ru(II) complexes. The in vitro potencies of all the complexes toward pancreatic cancer cell line MIA PaCa-2 are more than cisplatin (CDDP). The Pt(II) and Ru(II) complexes show similar binding constants with CT-DNA, but the reactivity of the Pt(II) complex 3 with 9-EtG is faster and their overall cell killing pathways are different. This is evident from the arrest of the cell cycle by the Ru(II) complex 1 in the G2/M phase in contrast to the SubG1 phase arrest by the Pt(II) complex 3. The immunoblot study shows that 3 increases cyclin D and Bcl-2 expression in MDA-MB-231 due to the SubG1 phase arrest where these proteins express in greater quantities. However, both 1 and 3 kill in the apoptotic pathway via dose-dependent activation of caspase 3. Complex 3 depolarizes the mitochondria more efficiently than 1, suggesting its higher preference for the intrinsic pathway of apoptosis. Our work reveals that the same bidentate ligand with a change of the metal center, viz, Pt(II) or Ru(II), imparts significant variation in cytotoxic dosage and pathway of action due to specific intrinsic properties of a metal center ( viz, coordination geometry, solution stability) manifested in a complex.