Synthesis and evaluation of bioactivable nitric oxide no donors

Abstract

Nitric oxide NO is an endogenously produced important biomolecule that is involved in various physiological processes that range from vasodialation to immunoregulation NO alongwith other reactive nitrogen species react with majority of biomolecules DNA proteins and lipids that leads to nitrosative and oxidative stress in cells The induction of nitrosative and oxidative stress is an important component of immunogenic role of NO Though the immunogenic role of NO in containing pathogens and in controlling growth of cancer cells have been studied for long time but yet not fully characterized In order to precisely study the role of NO inside cells reliable sources of NO that can selectively enhance intracellular NO levels are required Although numerous methodologies for NO delivery have been reported they are associated with certain limitations such as lack of specificity and tunability poor cell permeability and lack of a reporter for intracellular NO release The work in this thesis describes different approaches for reliably enhancing NO inside cells in a site specific manner and also monitoring intracellular NO with reporter based NO donor For selective delivery of NO inside cells firstly the bioreductive environment existing in cancer cells was exploited and enzyme activated NO donors which are substrates for bioreductive enzymes were synthesized DT Diaphorase DT D is a bioreductive enzyme known to be over expressed in certain solid tumors Using indolequinone scaffold INDQ NO was designed and synthesized as a possible substrate for DT D INDQ NO was found to be activated by DT D to generate NO Cellular assays revealed the capability of this compound to permeate cells to generate NO and damage DNA Secondly nitroreductase NTR a bacterial enzyme was chosen as a possible enzyme to activate NO donors NTR has been extensively used in designing prodrugs for the directed enzyme prodrug therapies and is thus of therapeutic interest 4 Nitrobenzyl based NO donors possible substrates for NTR were synthesized and st