Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Natural products continue to be one of the most important sources of new lead compounds for the discovery of medicinal agents. They occupy vast regions of chemical space, providing much greater diversity in their structures as well as their biological properties compared to those of classical drug molecules. Potent compounds from nature have provided paramount architectural inspiration for developing new chemical therapies, with more than 80% of all drugs and over 65% of anticancer drugs being, derived from, or inspired by natural products; however, their structural complexity and limited availability are often the sole obstacles preventing their further study and clinical development. As synthetic organic chemists situated at the interface of chemistry and biology, our research program is devoted to providing solutions to this supply problem in the form of sustainable and practical syntheses of complex biologically active natural products, and to performing fundamental studies of their chemical biology. By developing new synthetic strategies, as well as target-specific methodologies, we intend to provide efficient access to complex bioactive natural products and bring them within the realm of medicinal chemistry. Specifically, in this proposal we describe synthetic approaches to several diverse terpenoid natural product classes: isomalabaricane triterpenoids, nimbolide, and a vast range of perhydrobenz[e]indene-based terpenoids. We already established stereodivergent access to all four challenging stereoisomers of the rare 6/6/5 tricyclic terpenoid core structure that occurs in nature. Moreover, we recently completed several isomalabaricanes, using synthetic blueprint that permits rapid diversification. We are beginning to engage in biological investigations, and our ongoing collaboration with chemical biology experts will provide an excellent opportunity to test these compounds and their analogues for therapeutic activities, as well as to elucidate their mechanisms of action, molecular targets, and metabolites. It is expected that these studies will provide anticancer and anti-infective agents with unprecedented molecular topologies and functions, as well as advance our basic knowledge of their mechanistic specificity for certain cancers and pathogenic diseases.
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