ALL RIGHTS RESERVED DESIGN AND SYNTHESIS OF NOVEL SMALL MOLECULE MODULATORS OF KEAP1-NRF2-ARE PATHWAY ABSTRACT OF THE DISSERTATION DESIGN AND SYNTHESIS OF NOVEL SMALL MOLECULE MODULATORS OF KEAP1-NRF2-ARE PATHWAY

Lin Chen, Lin Chen, Lin Chen, Yanhui Inoyama, Sadagopan Yang, Herve Magesh, Jing Aloysius, Dhulfiqar Zhen, Ali
2014 unpublished
Keap1-Nrf2-ARE system represents a key signaling pathway in the regulation of cellular defense mechanisms against oxidative stress and inflammation. Activation of Keap1-Nrf2-ARE system can induce the expression of a number of antioxidant defense enzymes and proteins critical for preventing oxidative damage, inflammation and tumorigenesis. Curcumin exhibits antioxidant, anti-inflammatory and anti-carcinogenic properties and is demonstrated as an indirect inhibitor of Keap1-Nrf2 protein-protein
more » ... teraction. Novel classes of iminothiazinylbutadienols and divinylpyrimidinethiones were designed and synthesized as analogs of curcumin with its β-diketone moiety masked as a heterocyclic adduct with thiourea. The chemical stability of these novel heterocyclic compounds was improved as compared to curcumin. The biological activity evaluations revealed that some of these new curcumin analogs are more effective ARE activators than curcumin and isothiocyanates. iii Most available modulators of Keap1-Nrf2-ARE pathway modify the cysteine sulfhydryl groups of Keap1 for ARE activation. There are safety concerns about these thiol-reactive compounds. A high-throughput screen (HTS) of the MLPCN library identified the first-in-class inhibitor specifically for the direct inhibition of the Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers and the active stereoisomer was designated as LH601A and its stereochemistry was confirmed by X-ray crystallography and stereospecific synthesis. Various analogs of LH601A were designed and synthesized to improve the binding affinity. The obtained structure activity relationships (SAR) provided guidance for further structural optimization. Several analogs showed to be more potent than LH601A. These direct Keap1-Nrf2 inhibitors can mimic the actions of electrophiles in the induction of cytoprotective enzymes but are more selective and specific. Therefore, these direct inhibitors of Keap1-Nrf2 protein-protein interaction have great potential to be developed into innovative therapeutic agents for many diseases and conditions involving oxidative stress. iv ACKNOWLEDGEMENTS I would like to express my appreciation to a number of people for their help with this doctoral dissertation. First of all, I would like to express my sincere gratitude to my advisor, Dr. Longqin Hu, for his support, instruction, guidance and encouragement throughout my graduate studies and researches. It is my fortune to find an advisor who is always providing stimulating research ideas, equipping the laboratory with many modern instruments that not only make my work more efficient but also helped me be familiarized with the latest technology in pharmaceutical industry. Dr. Hu is also an encouraging example who lead me to overcome all kinds of difficulties and gain not only the traditional medicinal chemistry knowledge but also the skills to solve encountered problems during research. His fruitful discussions and constructive comments were essential to the completion of this dissertation, and he has taught me innumerable lessons and insights on the workings of research and how to be successful in career and life.
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