Gary A. Sulikowski
Natural product total synthesis. We have maintained a longstanding interest in the development of synthetic strategies leading to the total synthesis of complex natural products. Historically, natural products present opportunities to address defined synthetic challenges presented in the novel structure of a natural product target. Currently we are pursuing the total synthesis of marine diterpenes (bielschowskysin) and alkylpiperidine alkaloids (upenamide and xestocyclamine A). These studies also serve as an excellent opportunity for the training of young scientists interested in the art and practice of chemical synthesis. Increasingly our motivation in the area of total synthesis is the biological study of synthetic products and derivatives (arachidonic acid metabolites and antimicrobial natural products).
Biology and chemistry of natural products. Natural products are among the most structurally complex and privileged of the bioactive small molecules. Analysis of the sources of small molecule drugs approved between 1981 and 2006 indicates that over half of the new chemical entities declared in this timeframe were natural products or derived from natural products. However, from the perspective of medicinal chemistry, the complex molecular architecture of natural products continues to pose a significant challenge to access not only quantities of the parent structure but also analogs to establish structure-activity relationships (SAR). In addition to utilizing our skills in chemical synthesis to access and modify natural products we also attempt to harness the biosynthetic machinery to access complex natural products, sometimes in collaboration with groups with expertise the genetic modification of biosynthetic pathways. We were the first group to identify the biosynthesis of the complex nonadrides CP-225,917 and CP-263,114 and study the development of this biosynthetic dimerization in the lab. More recently, working with the Bachmann group we have developed fluorescent derivatives the cell selective cytotoxic agent apoptolidin and demonstrated its localization in the mitochondria. We are also one of two groups in the world that developed a chemical synthesis of the microbial thiol bacillithiol, now being used by investigators worldwide.
Chemical probes and pre-clinical lead development. Phenotypic and functional screens of compound libraries are currently being used by a variety of biomedical investigators in Cell and Developmental Biology, Microbiology and Immunology and Pharmacology. We provide chemistry support in lead development and target identification studies. In some cases we have optimized lead potency and metabolic compound properties allowing animal studies to provide preliminary validation of new targets for therapeutic development.