Synthetic Chemistry Approaches to Solve Fundamental Biological Problems
David R. Calabrese, Ph.D.
National Cancer Institute
National Institutes of Health
CBC Faculty Candidate
Synthetic chemistry provides a method for probing biological systems via biosensors and drug development. This presentation Mixed polymer brushes, substrates that have two or more types of polymers attached to the surface, have been employed as medical devices and biosensing tools. However, achieving two or more uniformly disperse polymers chains on the surface is a challenge. In my graduate research, I designed a new, easy to synthesize, Y-shaped polymer initiator that anchored to the surface and forced two different types of polymers to be “grown” from the same location creating a heterogeneous surface. This new initiator created improved surfaces and is being incorporated for biosensor applications.
Synthesizing small molecules that bind to and alter the function of regulatory nucleic acid sequences is particularly attractive when they govern the expression of so-called “undruggable” proteins, such as the oncoprotein c-MYC. We used small molecule microarrays, a surface chemistry technique, to quickly profile tens of thousands of compounds and identified a molecule that selectively bound to MYC DNA and downregulated MYC expression in multiple myeloma cells. Through rational design, I developed a new synthetic route to produce analogs of the original hit and helped to solve the NMR structure of the optimized small molecule binding to a nucleic acid sequence in the MYC promoter. Taken together, the work described in this presentation demonstrates that synthetic chemistry can be utilized to create new platforms and provide chemical and structural insights for solving complex biological problems.