Executive Summary : | The increasing number of cancer patients has sparked a growing interest in anticancer drug development, but current Pt-based chemotherapeutics face adverse side effects and drug resistance. To ensure the sustainability of future generations, new avenues are needed for metal-based catalytic anticancer drugs that disrupt cellular redox and metabolic balance, reducing inherent metal toxicity. Metalloenzymes catalyze biochemical transformations in cells, but their stability in a complex cellular environment is challenging. Recently, 16 electron Os(II) complexes have been introduced for in-cell transfer hydrogenation of pyruvate, showing better catalytic anticancer performance than Ru(II) complexes. However, their potential for in-cell NAD+ reduction is yet to be explored. To address these shortcomings, a proposal is being proposed to develop photoactive, 18 electron, tethered Os(II) pro-catalysts of type [Os(η6-Ph(CH2)n-ethylenediamine)X]Cl. These pro-catalysts will be converted into the active catalyst at the tumor site on light exposure, leaving normal cells unaffected. Tethered ligands are known to enhance the stability of metal complexes, and the proposed complexes will not react with intracellular nucleophiles, minimizing off-target reactivity. The possibility of f-formylmethionine as an alternate source of hydride is also being explored. The goal is to develop photoactive and stable Os(II) pro-catalysts for photo-triggered in-cell reductive stress generation to overcome the drawbacks of existing metal-based cancer drugs. |