CAREER: Exploring Novel Chemical Space: Modular Synthesis of Biologically Relevant Strained Molecules

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With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Tian Qin of University of Texas Southwestern Medical Center is aiming to develop new methods to access strained small molecules for potential application in investigational drugs. Such endeavors could empower practitioners of drug discovery to explore an expanded chemical space, accelerating the discovery of drug molecules with palatable drug-like properties. By way of example, bicyclo[1.1.1]pentane (BCP), a strained hydrocarbon molecule, is identified as a three-dimensional surrogate for aromatics, which are commonly found in drug candidates but often contribute to unfavorable properties. To this end, BCP provides an attractive alternative to aromatics. However, the broader application and functionalization of this moiety is limited by a lack of readily accessible synthetic approaches. Dr. Qin's laboratory is developing a novel synthetic strategy to bridge this gap. This project lies at the interface of organic synthesis, theoretical chemistry, physical organic chemistry, and medicinal chemistry. It is thus well-suited for the education of aspiring scientists at all levels with diverse backgrounds. Broad participation in science, technology, engineering, and mathematics (STEM) education will be encouraged at the collegiate and K-12 levels, taking advantage of recent advances in modeling and visualization technologies.In this project, the Qin research team of UT Southwestern Medical Center is developing synthetic methods for pharmaceutically relevant strained bicyclic molecules. The bicyclo[1.1.1]pentane (BCP) motif has increasingly garnered interest in the medicinal chemistry community, due to its ability to improve the physicochemical properties of prospective drug candidates, as a bioisosteric replacement of aromatic rings. Although several methodologies have been reported to prepare multi-substituted BCPs, access to bridge-substituted BCPs has been limited. The proposed research leverages a series of novel BCPs reagents to facilitate the synthesis and probe new reactivities of this strained ring system. Three specific aims are under concurrent investigation in this project to provide (i) access to complex multi-substituted caged bicyclic molecules, (2) systematic optimization of synthetic approaches to BCPs, and (3) knowledge of the properties of multi-substituted BCPs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.