Compounds from nature (natural products) continue to be one of the most important sources of new lead compounds in the discovery of medicinal agents. They occupy vast regions of chemical space, providing much greater diversity in their structure as well as 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 de...

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Compounds from nature (natural products) continue to be one of the most important sources of new lead compounds in the discovery of medicinal agents. They occupy vast regions of chemical space, providing much greater diversity in their structure as well as 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. Specifically, in this CPRIT proposal, we describe synthetic approaches and biological investigations of several diverse and unexplored anticancer natural products, ranging from terpenoids to alkaloids. By developing new strategies, as well as target-specific methodologies, we intend to provide efficient access to bioactive analogs and molecular probes and bring them within the realm of medicinal chemistry. This will provide many opportunities to evaluate these compounds for therapeutic activities, as well as to elucidate their mechanisms of action and molecular targets. It is expected that these studies will provide anticancer agents with unprecedented molecular topologies and functions, as well as advance our basic knowledge of their mechanistic specificity for certain cancers.

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