Synthetic and biological studies of understudied anti-tubercular natural products

描述（申请人提供）：结核病是一种毁灭性的疾病，每年造成100多万人死亡。尽管事实上超过20%的结核病病例用标准抗生素是不可治疗的，但在超过40年的时间里没有新的结核病特异性药物被引入临床实践。 最近，从植物桂（Cinnamomum kotoense）的茎材中分离到两种结构相关的天然产物，它们能够抑制M.结核病在低微摩尔浓度。重要的是，虽然这些分子在结构上彼此相似，但它们与任何结核病药物都没有结构相似性 在今天的市场上。在此，我们建议开发这些抗结核小分子的简单且可扩展的合成路线，并进行初步的结构-活性关系研究，以阐明两种靶标之间共同的特定结构特征的重要性。 为实现这一目标，我们将开展以下具体工作：（1）完成天然产物林可酮B的首次全合成，并开发互补的Cram螯合Baylis-Hillman反应以提高该过程的效率;（2）完成天然产物酮内酯A的首次全合成。为了有效地实现这一目标，一部小说？将开发羟基丁烯二醇/醛级联过程，其将在单个步骤中设置分子的所有必要立体中心;（3）将通过开发的合成获得天然产物的结构类似物，并且将针对M.结核病细胞系类似物将侧重于了解分子的共同亲脂性侧链，立体化学，以及两个目标共享的亲电性不饱和内酯的重要性。 拟议研究的长期目标是开发结核病治疗的新疗法。对天然产物的合成研究将使这一目标的深远生物学研究成为可能，初步的生物学实验将揭示可用于设计更深入药物开发追求的重要信息。此外，这些合成也将导致分子探针的发展，这将有助于阐明目前尚不清楚的天然产物的作用机制。从这些研究中获得的信息可能会发现结核病治疗的新模式。

DESCRIPTION (provided by applicant): Tuberculosis is a devastating disease that kills over 1 million people each year. Despite the fact that over 20% of tuberculosis cases are untreatable with standard antibiotics, no new TB- specific drugs have been introduced into clinical practice in over 40 years. Recently, two structurally related natural products were isolated from the stem wood of the plant Cinnamomum kotoense that were capable of inhibiting the growth of M. tuberculosis at low micromolar concentrations. Importantly, while these molecules are structurally similar to one another, they have no structural similarities to any tuberculosis drugs on the market today. Herein, we propose the development of simple and scalable synthetic routes to these anti- tubercular small molecules and preliminary structure-activity relationship studies that will illuminate the importance of specific structural features common between the two targets. To achieve this goal, we will carry out the following specific aims: (1) The first toal synthesis of the natural product lincomolide B will be completed, and the development of a complementary Cram-chelate Baylis-Hillman reaction will be developed to improve upon the efficiency of the process; (2) The first total synthesis of the natural product kotolactone A will e carried out. To achieve this in an efficient manner, a novel ?-hydroxybutenolide/aldehyde cascade process will be developed that will set all of the necessary stereocenters of the molecule in a single step; (3) Structural analogs of the natural products will be accessed through the syntheses developed, and these molecules will be tested against a M. tuberculosis cell line. The analogs will focus on understanding the common lipophilic side chains of the molecules, the stereochemistry, and the importance of the electrophilic ¿,¿-unsaturated lactone that both targets share. The long-term goal of the proposed research is to develop new therapeutics for TB treatment. Synthetic studies on the natural products will enable far-reaching biological studies toward this goal, and preliminary biological experiments will uncover important information that can be exploited in the design of more in-depth drug development pursuits. Moreover, these syntheses will also lead to the development of molecular probes that will help elucidate the mechanism of action of the natural products, which is not currently known. Information resulting from these studies could uncover new paradigms for tuberculosis treatment.