Chalcone-based chemical probes as versatile tools for potential target identification and mechanism elucidation of chalcone’s bioactivities

University of Minnesota Ph.D. dissertation. April 2016. Major: Medicinal Chemistry. Advisor: Chengguo Xing. 1 computer file (PDF); xiii, 215 pages.Chalcone is an important family of plant-derived compounds. For decades it has attracted great research interest in the field of medicinal chemistry, partly due to its rich natural source, easy synthetic availability, and diverse biological activities. The well-documented biological activities of chalcones include anti-cancer, anti-inflammatory, anti-diabetic, cancer chemopreventive, anti-oxidant, and anti-microbial activities. Numerous studies have attempted to elucidate the mechanisms of action and target interactions responsible for these biological activities. Many putative molecular targets have been reported, which are reviewed in this thesis (Chapter 1). However, lack of evidence of direct target interaction in cells and their biological relevance presents an unmet challenge for chalcone’s mechanistic investigation and optimization. Given the diversity of various putative molecular targets, it is also debated whether chalcone is a privileged or promiscuous template for biological interaction. Therefore, further understanding and improvement of chalcone’s biological activities as well as its translational development are largely dependent on a better understanding of chalcone’s interaction with its direct cellular targets. To help address this, in this thesis, various chemical probe approaches have been explored to advance the current understanding of chalcone’s target interactions. Specifically, we designed a panel of chalcone-based fluorescent probes and photoaffinity probes (Chapter 2) with varied cytotoxic potencies to study the direct cellular targets responsible for chalcone’s cytotoxicity, which was unambiguously revealed as β-tubulin (Chapters 3-5). Besides, we developed a combinatorial synthetic method for the efficient construction of a focused library of chalcone-based photoaffinity probes, and studied their cellular target interaction profiles (Chapter 6), where several novel potential targets were revealed. Overall, our results showcase the usefulness of chemical probe approaches, particularly photoaffinity probes, in the target investigation of chalcone-based compound. These results strongly suggest that chalcone has the potential to be developed as a privileged template for biological interactions, and encourage future research endeavors to further study and optimize chalcone’s various biological activities