Synthetic and biological studies of understudied anti-tubercular natural products

正在研究的抗结核天然产物的合成和生物学研究

• 批准号: 8214046
• 负责人: Ryan Murelli
• 金额: $ 15.7万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214046
• 关键词: Address; Affect; Aldehydes; American; Antibiotics; Applications Grants; Biological; Biological Factors; Biology; Cell Line; Cinnamomum; Development; Disease; Drug Resistant Tuberculosis; Drug resistance; Extreme drug resistant tuberculosis; Foundations; Funding; Future; Goals; Growth; Health; Human; Kinetics; Lactones; Lead; Marketing; Medicine; Methodology; Methods; Molecular Probes; Mycobacterium tuberculosis; Pharmaceutical Preparations; Plants; Process; Public Health; Reaction; Research; Route; Side; Structure; Structure-Activity Relationship; Testing; Therapeutic; Tuberculosis; United States; Wood material; World Health; analog; base; career; chemical synthesis; clinical practice; design; drug development; improved; interest; killings; method development; novel; novel therapeutics; programs; research study; small molecule; stem; stereochemistry; synthetic construct; tool; tuberculosis drugs; tuberculosis treatment

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. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is a devastating disease that kills over 1 million people worldwide each year. Despite this fact, no new TB-specific drugs have been introduced into clinical practice in over 40 years. The proposed research could lead to the development of new treatment options for TB, and thus is of interest to public health.

描述(申请人提供)：结核病是一种毁灭性的疾病，每年导致100多万人死亡。尽管超过20%的结核病病例无法用标准抗生素治疗，但40多年来没有针对结核病的新药物进入临床实践。最近，从肉桂的茎木材中分离到了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之处 在今天的市场上。在此，我们建议开发简单且可扩展的合成路线来合成这些抗结核小分子，并进行初步的构效关系研究，以阐明两个靶点之间共同的特定结构特征的重要性。为了实现这一目标，我们将实现以下具体目标：(1)将完成天然产物林可内酯B的首次全合成，并将开发互补的Cram-螯合Baylis-Hillman反应，以提高该过程的效率；(2)将进行天然产物Kotolacone A的首次全合成。为了以有效的方式实现这一点，将开发一种新型的β-羟基丁烯内酯/醛的级联过程，该过程将在单一步骤中设置该分子的所有必要的立体中心；(3)将通过所开发的合成获得天然产物的结构类似物，并将针对结核分枝杆菌细胞系测试这些分子。类比将侧重于了解分子的常见亲脂侧链、立体化学以及两个目标共享的亲电、不饱和内酯的重要性。这项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朝着这一目标进行的深远的生物学研究成为可能，初步的生物学实验将揭示重要信息，可用于设计更深入的药物开发目标。此外，这些合成还将导致分子探针的开发，这将有助于阐明目前尚不清楚的天然产物的作用机制。这些研究产生的信息可能会发现结核病治疗的新范例。 公共卫生相关性：结核病(TB)是一种破坏性疾病，每年导致全球100多万人死亡。尽管如此，40多年来没有针对结核病的新药物进入临床实践。拟议的研究可能导致开发新的结核病治疗方案，因此对公共卫生有好处。