Synthesis and characterization of triruthenium carbonyl incorporating 4-pyridones as potential antitumor agents

Four new organometallic triruthenium carbonyl incorporating 4-pyridones: [Ru-3(CO)(8) (2L-2H)] (1, L = N-benzyl-3-hydroxy-2-methyl-4-pyridone; 2, L = 3-hydroxy-2-methyl-N-phenyl-4-pyridone; 3, L = 3-hydroxy-N,2-dimethyl-4-pyridone; 4, L = 2-methyl-4-pyridone) were synthesized and characterized. Proton NMR spectrum of 1 shows doublets for the two-nonequivalent benzylic hydrogens due to restricted rotation around C-N bond upon bonding to Ru(2)-Ru(3) as opposed to a singlet in the unbound N-benzyl-3-hydroxy-2-methyl-4-pyridone. Compounds 1 and 3 were characterized by X-ray diffraction analyses. Compounds 1 and 3 consists of two ruthenium-ruthenium bonds Ru(1)-Ru(2), Ru(1)-Ru(3) and a non-bonded separation of two ruthenium atoms defined by Ru(2) ... Ru(3), which is bridged by two 3 electron donar oxygen atoms through two-pyridinonato ligands above and below triruthenium plane, and 8 terminal CO groups. Atoms Ru(2) and Ru(3) ligated by two CO ligands each and Ru(1) with four. Antitumor activity of the compounds 1-4 has been evaluated against five types of human cancer cell lines. Compounds 1 and 2 show excellent antitumor activity due to lipophilic nature of N-substituted arene pyridinonato ligands than compounds 3 and 4. Structure-activity studies show that there is a correlation between the N-substituted arene pyridinonato ligands and an increase in activity following the order 1 > 2>3 > 4. The anticancer activity of compounds 1 and 2 is between 1-2 orders of magnitude more active than cisplatin. This is possibly due to substitution of CO ligands at Ru(1) by transferrin delivery vehicle transporting to cancer cells and lipophilic N-substituted arenes diffuse through lipophic membrane leading to apoptosis and other carbonyl groups under physiological conditions likely function as carbonyl releasing molecules (CORMS). (C) 2018 Elsevier B.V. All rights reserved.