Studies in bioorganic and medicinal chemistry

点击翻译按钮获取中文摘要

The primary focus of my research program is to develop new methods for synthesizing molecules that can be used in the construction of biologically important compounds and evaluate selected compounds as lead structures for the design of therapeutic agents and for elucidating mechanisms of medicinally significant enzymes. The first subject of this proposal concerns the synthesis of chiral organofluorines where the fluorine is attached to a stereogenic carbon. This will be achieved using a novel class of chiral N-fluorosulfonimides which we anticipate will act as enantioselective electrophilic fluorinating agents. Compounds resulting from these studies are important as they have potential as useful intermediates in organic synthesis and as probes and inhibitors of enzymes and other proteins. The second part of this proposal deals with the design, synthesis and evaluation of inhibitors of a class of enzymes know as sulfatases. One such sulfatase, steroid sulfatase (STS), is considered to be a potential target for the treatment of breast cancer. The mechanism of a series of novel fluorine-bearing, irreversible, suicide STS inhibitors will be elucidated and evaluated for their potential for performing live imaging of STS in breast cancer cell lines. Novel aldehyde-based irreversible active site directed inhibitors will also be explored. A new steroid binding site recently discovered as a result of our collaboration with a protein crystallographer will also be exploited for developing non-competitive STS inhibitors. We will also examine a series of unique fluorinated carbohydrate sulfonates as inhibitors of H. pylori sulfatase, an enzyme that is believed to contribute to the severity of gastric diseases caused by this bacterium. The third part of this proposal focuses on developing a new class of sulfating agents called sulfuryl imidazolium salts (SIS's) recently prepared for the first time in the Taylor laboratory. The next generation of SIS's will be prepared with superior stability and sulfating properties. These will be used to construct complex and physiologically important sulfated biomolecules such as sulfated oligosaccharides and peptides.