Science

Chemical synthesis plays an increasingly significant role in the advancement of the life sciences. Our program aims to explore and further advance this paradigm by developing enabling chemical transformations, translating chemical diversity to cell-regulatory function, and providing an arsenal of new small-molecule agents for basic and translational biomedical research.

Understanding the nature of reprogrammed energy metabolism in cancer cells is of significant current interest. Notable alterations of energy metabolism have been linked to aging and immune response. Our recent work identified leucascandrolide A and neopeltolide as potent inhibitors of cytochrome bc1 complex. This effort was enabled by the development of practical synthetic approaches to this class of marine natural products, as well as a series of genetic and biochemical studies in yeast and mammalian cells. Highly potent cell-based antiproliferative activity of leucascandrolide A and neopeltolide compares favorably to the most effective inhibitors of cytochrome bc1 complex known today, identifying such compounds as a new class of highly useful biochemical tools for investigation of eukaryotic energy metabolism.

Small molecules that bind to monomeric or filamentous actin elicit their antiproliferative effects by impairing the ability of cells to progress through the cell cycle and undergo cytokinesis due to the defective actin cytoskeleton. Understanding the mode of action of such compounds expands our knowledge of actin biochemistry and provides opportunities for the development of new therapeutic agents. We have developed a 15-step synthesis of bistramide A, established actin as the cellular target of this natural product, crystallized actin–bistramide complex, developed a detailed understanding of the structure-activity profile and established the mechanism of actin depolymerization. We are currently employing our extensive expertise in the chemical biology of bistramides to assemble a series of new simplified analogs and to examine the ability of these compounds to inhibit tumor growth in several mouse models.

While inhibition of protein synthesis has been exploited as a strategy for the development of antibiotics, this approach has not been employed by any of the approved anticancer agents. We developed a fully stereocontrolled synthesis of spirofungin A and demonstrated that this natural product, similarly to reveromycin A, inhibited isoleucyl-tRNA synthetase with extraordinary specificity. To understand the remarkable specificity of isoleucyl-tRNA synthetase inhibition, we are currently cloning, expressing and purifying human isoleucyl-tRNA synthetase, and crystallizing the protein-small molecule complex. In addition, we are assembling a series of analogs of spirofungin A in order to evaluate the ability of such compounds to inhibit cancer progression and tumor metastasis.

Our laboratory is also involved in the development of new synthetic methods and strategies for the efficient generation of highly diverse small-molecule libraries. Particular emphasis is placed on exploring the fundamental reactivity of electron rich alkynes to enable rapid assembly of a range of polycyclic structures. This work is carried out as a part of a newly established Chicago Tri-Institutional Center for Chemical Methods and Library Development (CTCMLD), which bridges seven research groups at three leading universities in the Chicago area. We have recently devised a practical protocol for rapid production of chemical libraries, which does not require any specialized equipment, and represents a highly economical and facile method for generating molecular diversity in high chemical purity. We demonstrated the generality of this strategy by the design and synthesis of several new chemical libraries. High-throughput screening of this compound collection has identified a series of new molecules that elicited desired phenotypic responses in several cell-based assays.