New Strategies for Anticancer and Antibacterial Drug Discovery

Natural products have long been a backbone of drug discovery, as these compounds tend to be more complex – as measured by the fraction of sp3-hybridized carbons, number of stereogenic centers, etc – when compared to compounds in commercial screening collections.  We have been working to construct collections of compounds through a strategy known as “Complexity-to-Diversity”, whereby natural products are used as the starting materials for complex molecule synthesis.  Through this strategy we have created close to 1000 compounds from natural products such as gibberellic acid, adrenosterone, quinine, pleuromutilin, abietic acid, sinomenine, limonin, and lycorine, and screening through this collection for novel bioactive compounds has been fruitful.  Recently, we have been using these compounds to discern the features important for compound accumulation in Gram-negative bacteria, as infections with these pathogens are becoming increasingly difficult to treat since it has been over 50 years since the last new class of antibiotics for these bacteria has been approved by the FDA. 

This lecture will describe our Complexity-to-Diversity strategy, the application of these compounds in discovering rules for Gram-negative penetrance, and the use of this information to create a number of novel classes of antibiotics with activity against Gram-negative bacteria. The lecture will also discuss some of our latest advances in anticancer drug discovery.