Studies in bioorganic and medicinal chemistry

我的研究计划的主要重点是开发合成分子的新方法，这些分子可用于构建生物学上重要的化合物，并评估选定的化合物作为治疗剂设计的先导结构，并阐明具有医学意义的酶的机制。 该提案的第一个主题涉及手性有机氟的合成，其中氟连接到立体碳。 这将实现使用一类新的手性N-氟磺酰亚胺，我们预计将作为对映选择性亲电氟化剂。 从这些研究中得到的化合物是重要的，因为它们具有作为有机合成中有用的中间体以及作为酶和其他蛋白质的探针和抑制剂的潜力。 该提案的第二部分涉及一类被称为硫酸酯酶的酶的抑制剂的设计、合成和评价。一种这样的硫酸酯酶，类固醇硫酸酯酶（STS），被认为是用于治疗乳腺癌的潜在靶标。 一系列新的含氟，不可逆的，自杀STS抑制剂的机制将被阐明和评估其潜力，在乳腺癌细胞系中进行STS的活成像。 还将探索新的基于环糊精的不可逆活性位点定向抑制剂。 一个新的类固醇结合位点，最近发现的结果，我们的合作与蛋白质结晶也将被利用开发非竞争性STS抑制剂。 我们还将研究一系列独特的氟化碳水化合物磺酸盐作为H。幽门螺杆菌硫酸酯酶，这种酶被认为是导致由这种细菌引起的胃病严重性的原因。 本提案的第三部分着重于开发一类新的硫酸化剂，称为硫酰咪唑盐（SIS），最近在泰勒实验室首次制备。 下一代SIS将具有上级的稳定性和硫酸化性能。 这些将用于构建复杂的和生理上重要的硫酸化生物分子，如硫酸化寡糖和肽。

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.