Photoelectrocyclizations to Virulence Inhibiting Natural Products

耐药细菌的日益流行导致了对新方法的迫切需求 抗生素。特别是，小的发现和发展 不容易受到选择性压力的影响的分子，因此， 更少的耐药性发展机会，是当前感兴趣的话题， 我们相信我们可以帮助改变现状。这份提案概述了我们的计划， 专注于开发旨在破坏细菌通讯的新型支架， 毒性，尤其是革兰氏阳性菌。我们建议研究两种天然产物 引导分子经过联合收割机有机化学发展的四个阶段 方法与全合成和SAR。在这些努力的同时，将进行研究，其目标是 是为了确定我们的合成化合物控制毒性的能力。的选择 抑制剂开始我们的研究已经考虑到小分子的可及性 目标使用有效和新颖的化学合成方法，目标的活性 针对毒力靶标，包括分选酶A，以及化合物 抑制生物膜形成和破坏预先形成的生物膜。我们的领导结构是 discorhabdin Z是一种来自海绵Sceptrella的吡咯亚氨基醌天然产物 sp.和紫杉酮，一种松香烷家族的二萜天然产物， 鼠尾草这两种试剂都将使用独特的和 立体选择性双芳基烯烃光化学电环化反应顺序。我们将 继续开发和优化光电环化反应的过程中， 建议的努力。在程序的第三阶段，我们将生成 discorhabdin Z和紫杉酮旨在增强其毒力活性的同时进行回火， discorhabdin的细胞毒性。这里提出的工作的最后阶段 将与犹他州大学药物化学中心合作开展 设施，并将针对一个小组的测定，旨在收集信息的发展， 我们的所有化合物的抗生素活性、抗生物膜活性、分选酶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.