Photoelectrocyclizations to Virulence Inhibiting Natural Products

抗药性细菌的日益流行导致迫切需要新的治疗方法 为了抗菌剂。尤其是小卫星的发现和发展。 不那么容易受到选择压力的分子，因此，提供了 更少的发展阻力的机会，是一个当前感兴趣的话题，也是 我们相信，我们可以帮助做出改变。这份提案概述了我们的计划是 致力于开发新型支架，旨在扰乱细菌交流和 毒性，尤指革兰氏阳性细菌。我们建议研究两种天然产物 结合有机化学发展的四个阶段中的铅分子 方法论与全合成和合成孔径雷达。与这些努力同时进行的是研究，这些研究的目标是 是为了确定我们合成的化合物控制毒力的能力。选择 抑制剂开始我们的研究已经考虑到了小分子的可及性 靶标采用高效和新颖的化学合成方法，靶标的活性 针对毒力靶标，包括索酸酶A，以及化合物对 抑制生物膜的形成和破坏预先形成的生物膜。我们的主要结构是 Discorhabdin Z，一种来自海洋海绵Sceptrella的吡咯亚氨基醌天然产品 SP.紫杉酮，一种松烷家族的二萜天然产物，来自紫杉根 鼠尾草鼠尾草。这两种药物都将使用一种独特的 立体选择性双芳基烯光电化学环化反应序列。我们会 在以下过程中继续开发和优化光电环化反应 建议的努力。在程序的第三阶段，我们将生成类似的 Discorhabdin Z和紫杉酮旨在增强其毒力活性，同时回火， 对于不和谐蛋白来说，它们的细胞毒性。在此提出的工作的最后阶段 将与犹他大学药物化学核心合作进行 设施，并将致力于开发一组分析，旨在收集关于 我们所有的抗菌活性、抗生物被膜活性、分类酶A活性和毒性 合成化合物。

The increasing prevalence of drug resistant bacteria has resulted in a dire need for new approaches to antimicrobials. In particular, the discovery and development of small molecules that are not as predisposed to selective pressure and, as a consequence, offer fewer opportunities for the development of resistance, is a topic of current interest and one where we believe we can help to make a difference. This proposal outlines our program is concentrated on developing novel scaffolds aimed at disrupting bacterial communication and virulence, especially in gram-positive bacteria. We propose to study two natural product lead molecules over the course of four phases that combine the development of organic chemistry methodology with total synthesis and SAR. Concurrent to these efforts will be studies whose goals are to ascertain the ability of our synthetic compounds to control virulence. The choice of inhibitors to begin our studies has taken into account the accessibility of the small molecule targets using efficient and novel chemical synthesis methodology, the activity of the targets against virulence targets, including sortase A, and the ability of the compounds to inhibit biofilm formation and to disrupt preformed biofilms. Our lead structures are discorhabdin Z, a pyrroloiminoquinone natural product that comes from the marine sponge, Sceptrella sp. and taxodone, a diterpene natural product of the abietane family that comes from the roots of the sage Salvia austriaca. Both of these agents will synthesized using a unique and stereoselective bis-aryl alkene photochemical electrocyclization reaction sequence. We will continue to develop and optimize the photoelectrocyclization reactions over the course of the proposed efforts. In the third phase of the program we will generate analogs of discorhabdin Z and taxodone aimed at enhancing their virulence activity while tempering, for the discorhabdins, their cytotoxicity. The final phase of the work proposed here will be carried out in collaboration with the University of Utah Medicinal Chemistry Core Facility and will target the development of a panel of assays aimed at gathering information about the antibiotic activity, anti-biofilm activity, sortase A activity, and toxicity of all of our synthetic compounds.