Organosulfates and Polyphosphates: Their Synthesis and the Enzymes that Process Them.

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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 sulfated carbohydrates. This is an extremely important class of biomolecules as they play key roles in numerous important biological processes such as blood clotting and the immune response. We have developed a new approach to preparing these compounds which employs monosaccharides bearing protected sulfodiesters as building blocks. To determine the scope of this methodology, studies on the regioselective incorporation of protected sulfodiesters into monosaccharide building blocks as well as the effect of protected sulfodiesters on glycosylation reactions will be performed. The total synthesis of two complex multisulfated oligosaccharides will also be achieved. The second part of this proposal deals with the design, synthesis and evaluation of inhibitors of steroid sulfatase (STS), an enzyme involved in the storage of estrogens. Inhibitors of STS are being examined as therapeutics for treating of breast cancer. We have prepared very potent reversible and irreversible inhibitors of STS. We will determine how these inhibitors bind to STS using photoaffinity labeling, modeling, NMR and x-ray crystallographic analyses. The mechanism of substrate entry and product release in STS will also be studied. In the third part of this proposal intermediate and transition state analogs of the reaction catalyzed by cytidine triphosphate synthase (CTPS), an anticancer and antiviral target, will be constructed using a novel and powerful phosphorylation procedure recently developed in our group. These compounds will be used to determine which residues are important for ligand binding and intermediate and transition state stabilization in the CTPS reaction. These results of these studies will provide information that will be crucial for developing drugs that target CTPS.