Synthetic and biological studies of understudied anti-tubercular natural products

描述（由申请人提供）：结核病是一种毁灭性疾病，每年导致100多万人死亡。尽管20%以上的结核病病例无法用标准抗生素治疗，但40多年来没有将新的结核病特异性药物引入临床实践。最近，从植物Cinnamomum kotoense的茎材中分离出两种结构相关的天然产物，它们能够在低微摩尔浓度下抑制结核分枝杆菌的生长。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在结构上没有相似性

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.