Synthesis And Biological Evaluation Of Nitrile-Based Inhibitors Of Cysteine Proteases Caged With Ruthenium Complexes

Light activated compounds can be used as tools for understanding and solving numerous biological problems. This dissertation focuses on developing ruthenium-based photocages for caging nitrile-based cysteine protease inhibitors. Four research areas pertaining to this dissertation, i) metals in medicine, ii) photocages in biological applications, iii) photodynamic therapy and iv) cysteine cathepsin proteases were briefly surveyed in the introductory chapter. Next, RuII(bpy)2 group was utilized for synthesizing nitrile-based caged CTSK and CTSB inhibitors. Light activated release of inhibitors, followed by toxicity and stability data were studied. Cathepsin enzyme activity inhibition in 2D and 3D assays were established. This work showcased the applicability of ruthenium complexes in photocaging cathepsin inhibitors for gaining spatiotemporal control over enzyme inhibition. Later we reported that ruthenium (II) tri(2-pyridylmethyl)amine, a polypyridyl ligand distinct from the established Ru(bpy)2 class, is an effective caging group for nitriles that provides high levels of control over cathepsin activity with light. Also a library approach was developed by solid phase that provides rapid access to new complexes for screening photochemical behavior. Ligands designed to tune spectral properties of the ruthenium-based photocaging group were synthesized in parallel fashion on resin. The library was processed to form caged ruthenium complexes bound to resin, then subsequently cleaved and analyzed for photochemical reactivity. Three compounds identified from this screen were synthesized by solution phase and characterized spectroscopically and photochemically. Data were in good agreement with compounds from solid phase, thus validating the predictive power of our library approach. Finally new ruthenium complexes based on TQA ligand were developed and studied for solar cell applications