Use of anethole-type ligands to design cytotoxic organometallic ruthenium compounds: an experimental and computational study

Abstract

Two hitherto unknown organometallic compounds with antitumor activity, [Ru(eta(6)-2-(1-propenyl)anisole)(en)(Cl)]PF6 (3) and [Ru(eta(6)-2-(1-propenyl)anisole)(en)(l)]PF6 (4), where en is ethylenediamine, were synthesized and completely characterized using standard techniques (H-1 and C-13 NMR, high-resolution MS and elemental analysis). The lipophilicity and hydrolysis rate kinetics were assessed and compared to the previously reported [Ru(eta(6)-4-(1-propenyl)anisole)(en)(halogen)]PF6 derivatives (4-(1-propenyl)anisole or anethole), where the halogen is Cl (1) or I (2). Based on the obtained rate constants, the coordination of (1-propenyl)anisole to the Ru(en) moiety yielded organometallic compounds that are as active as compounds that bind p-cymene as the arene ligand. Consistent with previously reported kinetic data, our density functional theory-based computational study revealed that an associative interchange mechanism predominates in the hydrolysis of this type of compound, and only small variations (similar to 1 kcal mol(-1)) were observed between the stabilities of the transition states corresponding to different derivatives. In vitro analyses of the anti-proliferative activity revealed that compounds 1 to 3 generally exhibit better cytotoxicity and selectivity (tumor versus non tumor cells) toward the gastric tumor cell lines AGS and SNU-1, compared to the parent [Ru(eta(6)-p-cymene)(en)X]PF6 (X: Cl and I) systems. Compound 3 showed similar cytotoxicity to compound 1 toward the AGS cell line, indicating that the change in the substitution pattern of the coordinated arene from 4-(1-propenyl)anisole to 2-(1-propenyl)anisole did not prominently affect the biological behavior. Compound 2 remained the most promising candidate to treat gastric cancer