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Research Interests
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Research Overview Research in the Taylor group is interdisciplinary ranging from synthetic and medicinal chemistry to enzymology. We develop new synthetic methodology and then apply this methodology to the synthesis of modified biomolecules such as novel steroids, carbohydrates, amino acids, nucleosides and nucleotides. Many of the compounds we prepare are designed to be biophysical probes and inhibitors of medicinally significant enzymes such as steroid sulfatase (breast cancer), protein tyrosine phosphates 1B (diabetes) and cytidine triphosphate synthetase (anti-cancer and anti-viral target). We evaluate the compounds for in vitro biological activity and the results of these studies provide information on fundamental processes of biocatalysis and/or are used as lead structures for the development of useful therapeutics. Collaborations with protein x-ray crystallographers enable us to obtain the structure of our inhibitors bound to these enzymes and we use this information to develop the next generation of inhibitors. A wide variety of techniques are employed such as NMR, fluorimetry, HPLC, protein purification, spectrophotometry, and biological mass spectrometry. Organic Synthesis A significant part our effort in synthetic organic chemistry is directed towards the development of new synthetic methodologies. For example, we have developed an entirely new class of compounds called sulfuryl imidazolium salts (SIS’s) (Angew. Chem. Int. Ed. Engl., 2006, 3503) which are the first new class of sulfating agents to appear in over 40 years. We developed the first protecting group for arylsulfates (Org. Lett. 2004, 6, 209). We are now using SIS’s bearing this protecting group to construct complex sulfated biomolecules which are not readily attainable by traditional sulfation chemistry. We have also developed new approaches for synthesizing organofluorines compounds (approximately 8% of all drugs contain fluorine) by electrophilic fluorination (for example see: Org. Lett. 2004, 6, 4285). Our current work in this area focuses on the asymmetric synthesis of organofluorines, where fluorine is attached to a stereogenic carbon. To achieve this we are preparing chiral electrophilic fluorinating agents and examining them as reagents for performing enantioselective electrophilic fluorinations.
The other component of our research effort in organic synthesis involves the application of our methodologies to the synthesis of modified biomolecules such as novel steroids (J. Org. Chem. 2007; in press, Org. Biomol. Chem. 2005, 3, 3329), carbohydrates (Org. Lett., 2006, 8, 5617; Angew. Chem. Int. Ed. Engl., 2006, 3503, Carbohydrate Res. 2005, 340, 1213) nucleosides/nucleotides (J. Org. Chem. 2006, 71, 9420; Org. Lett. 2006, 8, 4243) and amino acids (J. Org. Chem. 2006; 71, 8190; Org. Lett. 2001, 3, 1571) We are currently using our methodologies to prepare some complex and highly interesting compounds such as the multisulfated tetrasaccharide known as CS-D (a neurite outgrowth promoter), and a highly unusual transition state-product analog of the reaction catalyzed by the enzyme cytidine triphosphate synthetase (CTPS).
Probes and Inhibitors of Medicinally Significant Enzymes
Steroid sulfatase (STS). STS catalyzes the desulfation of steroidal sulfates which are the storage forms of many steroids such as the female hormone estrone. Inhibitors of STS have potential as therapeutics for treating steroid-dependent breast cancer. We have developed a variety of novel reversible STS inhibitors (Bioorg. Med. Chem., 2006, 14, 8564, Org. Biomol. Chem. 2005, 3, 3329; Bioorg. Med. Chem. Lett. 2004, 14, 151). We collaborate with Dr. Debashis Ghosh, an X-ray crystallographer at the Hauptmann-Woodward Research Institute in Buffalo, New York, to obtain the structure of STS in complex with our inhibitors (for example see Figure 1). We have also developed some unique irreversible mechanism-based STS inhibitors. We are currently using our mechanism-based approach to develop generic sulfatase inhibitors that will be used for activity-based proteomic profiling of sulfatases. Mechanistic studies on STS and other sulfatases using a novel fluorogenic substrate developed in our laboratory (Anal. Biochem. 2005, 340, 80) are also in progress. Other collaborators on this project includes Dr. James Thomas at Mercer University School of Medicine (USA), who is testing the cytotoxicity of our inhibitors on steroid-dependent breast cancer cell lines.
Protein Tyrosine Phosphatase 1B (PTP1B). PTP1B catalyzes the dephosphorylation of phosphotyrosine residues in the insulin receptor kinase and is a key enzyme in the down regulation of insulin signaling. Inhibitors of PTP1B have tremendous potential as therapeutics for treating type II diabetes mellitus. Different tactics to inhibitor design are employed such as the substrate analog approach (J. Org. Chem. 2006; 71, 8190; Bioorg Med Chem. 2002, 12, 3471; Bioorg. Med. Chem. 2002, 10, 2309-2323) and in silico screening of virtual libraries and molecular modeling. Collaborations with protein crystallographers enable us to learn how our inhibitors interact with PTP1B (Figure 2. See also: J. Med. Chem. 2001, 44, 4584).
Cytidine triphosphate synthetase (CTPS). CTPS catalyzes the conversion of UTP to CTP (Figure 3). It is a very important enzyme as it is involved in the biosynthesis of pyrimidine nucleotides and is therefore a promising target for cancer and anti-viral therapy. Our current efforts are focused on constructing inhibitors that resemble
Figure 3. Reaction catalyzed by CTPS. transition states or intermediates of the reaction such as compounds 3 and 4 below (J. Org. Chem. 2006, 71, 9420; Org. Lett. 2006, 8, 4243). This project is in collaboration with Professor Stephen Bearne in the Dept. of Biochemistry and Molecular Biology at Dalhousie University.
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