Abstract
Ruthenium complex-protein interaction, particularly with respect to modulation of the enzymes associated to tumor development, is an evolving concept in understanding the mechanism of action of these complexes as anticancer agent. Lactate dehydrogenase (LDH; EC: 1.1.1.27) is critically implicated in maintaining tumor growth via ‘Warburg effect’ in cancerous cells. This article presents current status of Rucomplexes as enzyme inhibitors in general and a state of art on a novel ruthenium(II) complex containing 4- Carboxy-N-ethylbenzamide as an inhibitor of LDH. The 4-carboxy-N-ethylbenzamide (CNEB) was synthesized and characterized by single crystal X-ray measurement and complexed with cis-Ru(bpy)2Cl2.2H2O (bpy=2,2bipyridine) resulting into synthesis of a [Ru(CNEB)2(bpy)2] 2PF6.0.5 NH4PF6] complex, Ru(II)- CNEB. The complex showed appreciable cytotoxicity on Daltons lymphoma cells and a significant Ru(II)- CNEB-LDH interaction (Kc = 1.525 x 105 M-1). The later was further confirmed from luminescence quenching and gel retardation assays. The complex also caused a significant decline in the activities of purified LDH and LDH from mice liver extract. The complex was further characterized as a non-competitive inhibitor of LDH (Ki = 0.032 mM). Ru(II)-CNEB complex perfused mice liver also showed a significant decline in LDH activity coinciding with similar changes in the intensity of LDH bands on polyacrylamide gel electrophoresis. Thus, Ru(II)-CNEB complex, as a non-competitive inhibitor of LDH, seems to be a candidate for potential therapeutic applications.
Keywords: CNEB, Ru(II) complex, structural characterization, lactate dehydrogenase, metallodrug-protein interaction, gel mobility shift, enzymatic modulation, glycolytic enzymes, Warburg effect
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