Executive Summary : | Many chemical and pharmaceutical biocatalytic processes employ NADH and NADPH as cofactors. Chiefly, they represent the role of hydride sources in many biological reductions and, it would be extremely advantageous to rejuvenate them, given their high cost. NAD+ is a noteworthy co-enzyme that is involved in the maintenance of the cellular redox balance, the Kerb’s cycle and other metabolic pathways such as synthesis of ADP-ribose and its polymers and cyclic ADP-ribose that are fundamental for genome stability, DNA repair, and safeguarding calcium homeostasis. The perturbations in cellular redox level perform an important role in cell viability. Specifically, tumour cells are much more sensitive to this perturbation since they are already under constant oxidative stress owning to the production of high levels of reactive oxygen species. One of the vital components of cellular energy pathways and to cancer cells is pyruvate. Literature states that cancer cells generally utilize high levels of glucose as they are rapidly multiplying and thereby need to generate nutrients such as nucleotides and amino acids. This behaviour has been linked to mitochondrial malfunction. For a higher rate of glycolysis, cancer cells need higher levels of NAD+, which is regenerated by them at a very fast rate by reducing pyruvate to lactate. Based on this, we propose that upon treatment of our Ru(II)-arene complexes, the pyruvate present in the cancer cells may be diminished as the complexes may catalyze them to lactate. Subsequently, the regeneration of NAD+ and the anaerobic glycolysis that take place in cancer cells may be arrested. These processes, i.e., the pyruvate and NAD+ reduction, will be aided by our complexes, that will not only affect the cellular redox processes, but however will also hinder the ATP (energy) generation and production of various nutrients that are required by the cancer cells for progression. In particular, the success in the latter reaction seems to be strictly related to the presence of the NH functionality that allows the establishment of beneficial intermolecular hydrogen bonding between the HCOO- and catalyst, which was one of the key considerations while designing the ligand. The objective of the present proposal is to synthesize N,N-coordinating pseudo-thiourea/thiosemicarbazone ligands (L) and their corresponding Ru-arene complexes and study their capability as TH catalysts for biological substrates following which their anticancer potential will be explored. The experiments will involve synthesis and characterization of the complexes using spectroscopic and XRD tools. The activity of the complexes in TH will be monitored using GC-MS, UV-Visible and NMR spectroscopy. The anticancer activity will be studied using MTT and various staining and flow cytometric analysis and a possible catalyst-activity relationship will be established. This might be the first report from India integrating TH catalysis and anticancer property. |