Studies in bioorganic and medicinal chemistry

我的研究计划的主要重点是开发新的方法来合成分子，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先导结构，用于设计治疗剂和阐明医学上重要的酶的机制。本提案的第一个主题涉及手性有机氟的合成，其中氟与立体碳相连。这将使用一类新的手性n -氟磺酰亚胺来实现，我们预计它将作为对映选择性亲电氟化剂。这些研究产生的化合物很重要，因为它们有潜力作为有机合成的有用中间体，以及酶和其他蛋白质的探针和抑制剂。本提案的第二部分涉及设计、合成和评价一类酶的抑制剂，称为硫酸酯酶。其中一种磺化酶，类固醇磺化酶（STS），被认为是治疗乳腺癌的潜在靶点。一系列新型含氟、不可逆、自杀性STS抑制剂的机制将被阐明并评估其在乳腺癌细胞系中进行STS实时成像的潜力。此外，还将探索新型醛基不可逆活性位点定向抑制剂。最近我们与蛋白质晶体学家合作发现的一个新的类固醇结合位点也将被用于开发非竞争性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幽门螺杆菌硫酸酯酶的抑制剂，这种酶被认为与这种细菌引起的胃病的严重程度有关。该提案的第三部分侧重于开发一类新的磺化剂，称为硫酰咪唑盐（SIS），最近在泰勒实验室首次制备。下一代SIS将具有优越的稳定性和硫化性能。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.