Design and synthesis of phenazines and indenoisoquinolines as cancer chemopreventive agents
Abstract
Cancer is the second leading cause of death in the US and worldwide. Even when several efforts have been made and much has been achieved the number of cancer cases is increasing across the globe. The mortality rates of some types of cancer still remain prohibitively high. Therefore, it would be desirable to find a more effective way to deal with the disease. A prevention approach would be ideal to eliminate or reduce he carcinogenesis problem. Chemoprevention aims to stop, delay or reverse the initiation and progression of cancer. This thesis focuses on the design and synthesis of phenazines and indenoisoquinolines as new chemopreventive agents. Not much work in the chemoprevention field has been made using these molecular entities; therefore, the research presented here is exploratory in nature. Various compounds have been synthesized and their SAR studied against a panel of chemopreventive targets. The phenazines were investigated against quinone reductases 1 and 2, inducible nitric oxide synthase and NFkB. The indenoisoquinolines were tested against quinone reductase 1, retinoid X receptor, and NFkB. The synthesis and biological evaluation of a phenazine natural product and its analogues is presented. The preparation of novel indenoisoquinolines bearing acidic, ester, cyano and halide moieties is described. Some key structural features for RXR transcriptional activation and NFκB inhibition are described. Finally, some of the prepared indenoisoquinolines were evaluated against two other targets: tyrosylphosphodiesterase 1 and topoisomerase 1. A basic SAR study of the compounds against these targets is presented.
Degree
Ph.D.
Advisors
Cushman, Purdue University.
Subject Area
Chemistry|Pharmacy sciences
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