Throughout history, naturally-occurring small molecules, also known as natural products, have inspired the development of many anticancer drugs, including Adriamycin, Oncovin, Taxol, and others. In the past five years, my laboratory has developed a unique research program that lies at the confluence of synthetic chemistry and synthetic biology by combining them in hybrid synthetic strategies towards bioactive natural product–including those with anticancer activities. Additionally, we have adapted these strategies to generate further analogues for medicinal chemistry optimization and chemical probe development to interrogate disease-relevant pathways in biology. This CPRIT proposal seeks to ...

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Throughout history, naturally-occurring small molecules, also known as natural products, have inspired the development of many anticancer drugs, including Adriamycin, Oncovin, Taxol, and others. In the past five years, my laboratory has developed a unique research program that lies at the confluence of synthetic chemistry and synthetic biology by combining them in hybrid synthetic strategies towards bioactive natural product–including those with anticancer activities. Additionally, we have adapted these strategies to generate further analogues for medicinal chemistry optimization and chemical probe development to interrogate disease-relevant pathways in biology. This CPRIT proposal seeks to align our technology and capability with cancer research, whereby we will apply our hybrid chemoenzymatic strategies to simplify access to rare natural products with anticancer properties. Strategies developed will be further applied in the generation of additional analogues to optimize the anticancer activities of the initial leads, as well as chemical probes with wide-ranging structures to elucidate novel modes of action and illuminate new pathways in cancer biology. This research program is expected to facilitate the development of new cancer chemotherapy agents. The three Aims of the proposal are: (1) Covalent inhibitor development through a hybrid chemoenzymatic strategy, (2) Synthetic and medicinal chemistry of cytotoxic terpenoids with unusual modes of action, and (3) Synthesis and medicinal chemistry of novel microtubule stabilizing agents. Aims 1 and 2 will pursue the syntheses of several natural products with potent cytotoxicity and underexplored or undefined modes of action, as well as probe derivatives to elucidate these pathways and define their relevance to cancer biology. Aim 3 will result in the development of new chemotherapies that can overcome the growing resistance to Taxol and epothilone treatments.

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