Synthesis of Natural and Unnatural Inhibitors of ftsZ

描述（由申请人提供）：本提案的目标是证明某些抗菌天然产物的生物活性来自对ftsZ的抑制，ftsZ是细菌细胞分裂所需的哺乳动物微管蛋白的细菌类似物。FtsZ是开发对抗细菌感染的新方法的一个令人兴奋的新靶点，目前其他形式的治疗都对细菌感染有抗药性。迄今为止，很少有小分子被证明能抑制ftsZ，而少数能抑制ftsZ的小分子对哺乳动物细胞是有毒的。ICCB的研究发现了几种抑制ftsZ的新小分子，其中1种与一系列已知的抗生素天然产物具有共同的核心结构。这些天然产品是从目前用于传统药物的植物提取物中提取的，因此很可能对哺乳动物的毒性很低。我们将合成这些天然产物，以便识别它们的生物作用方式。在此过程中，我们将开发新的高效化学反应，使核心结构能够快速灵活地组装，并将这些合成技术以多样性为导向的方法用于各种结构类似物。如果成功，这一提议将证明植物衍生化合物及其合成类似物将抑制ftsZ，并为发现利用这种独特活性模式的化合物提供一些治疗价值的希望。

DESCRIPTION (provided by applicant): The goal of this proposal is to demonstrate that certain antimicrobial natural products derive their biological activity from inhibition of ftsZ, the bacterial analog of mammalian tubulin that is required for bacterial cell division. FtsZ is an exciting new target for developing new methods of combating bacterial infections that are currently resistant to other forms of therapy. To date, very few small molecules have been shown to inhibit ftsZ, and the few that do so are toxic to mammalian cells. Research at the ICCB has revealed several new small molecules that inhibit ftsZ, 1 of which shares a common core structure with a series of known antibiotic natural products. These natural products are derived from plant extracts that are currently used for traditional medicine, so it is likely that there mammalian toxicity is quite low. We will synthesize these natural products so that their biological mode of action can be discerned. In the process, we will develop new and highly efficient chemical reactions that allow rapid and flexible assembly of the core structures, and use these synthetic techniques in a diversity-oriented approach to a variety of structural analogs. If successful, this proposal will demonstrate that plant-derived compounds, as well as synthetic analogs thereof, will inhibit ftsZ and offer some hope of discovering compounds that exploit this unique mode of activity for therapeutic value.