Abstract
While metallodrugs such as cis-platin have demonstrated efficient activity in clinical application as anticancer drugs, their selectivity to cancer cells and understanding of their mode of action however remain a major challenge. Taking into consideration the desirable nature of 1,2,3- triazole derivatives both in catalysis as ligands and medicinal applications, attempts were made in this work to address toxicity and selectivity issues by design of new N^N platinum group metal (PGM)-based complexes. The complexes were then evaluated for their anticancer activity and possible relationship between cytotoxicity and catalytic activity under modeled aqueous condition in efforts to understand their possible mode of action. In this study, we report on the synthesis of a series of N^N Ru(II), Os(II), Rh(III) and Ir(III) derivatives of 1,4-disubstituted 1,2,3-triazoles, their cytotoxicity to a number of cancer cells (mainly lung A549, Kidney adenocarcinoma HEK293, cervical carcinoma HeLa and leukemia MT4) and their catalytic studies with respect to their observed biological activities. In this work, four triazole ligands (L1-L4) were synthesized and characterized by various analytical techniques which included Nuclear Magnetic Resonance (NMR) Spectroscopy, Mass Spectrometry (MS-ESI), Infrared Spectroscopy (IR) where applicable and Elemental Analysis (EA). Reaction of ligands L1-L4 with various metal precursors mainly [Ru(p-cymene)Cl2]2, [Os(p-cymene)Cl2]2, [Rh(Cp*)Cl2]2, and [Ir(Cp*)Cl2]2 gave a series of 20 cationic complexes (C1-C20) with counter-ions including Cl-, BF4 - and BPh4 -. The representative complexes C8 - C11 which are respective Ru(II), Os(II), Rh(III) and Ir(III) derivatives of L2 were evaluated for their catalytic activity to reduce both acetophenone and sodium pyruvate as substrates using sodium formate as a hydrogen source under aqueous conditions (phosphate buffered saline, pH 7.4). All the complexes were inactive in the reduction of acetophenone to 1-phenylethanol with only trace amounts of the product formed (≤ 0.5 % conversion) possibly contributed by their poor solubility in phosphate buffered saline. However, reduction of pyruvate to lactate gave conversions greater than 80 %. Complexes C8, C11 and C18 were found to be stable under aqueous conditions in a 10% DMSO phosphate buffer D2O at 37 oC, we observed no significant changes in the 1H and 31P NMR even over 72 hours...
M.Sc. (Chemistry)