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（由申请人提供）：结核病是一种毁灭性疾病，每年导致超过 100 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，但目前尚未将新的结核病特异性药物引入临床实践。最近，从Cinnamomum kotoense植物的茎木中分离出两种结构相关的天然产物，它们能够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都没有结构相似之处。 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，以阐明这两个目标之间共同的特定结构特征的重要性。 ，我们将实现以下具体目标：（1）完成天然产物林可莫内酯B的首次全合成，并开发互补的Cram螯合物Baylis-Hillman反应，以提高合成效率。 (2) 将进行天然产物 kotolactone A 的首次全合成 为了以有效的方式实现这一目标，将开发一种新颖的 β-羟基丁烯内酯/醛级联工艺，该工艺将在分子中设置所有必要的立体中心。 (3) 通过所开发的合成方法将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对这些分子进行测试。了解分子的常见亲脂侧链、立体化学以及亲电子的重要性 ¿ ,¿两个靶点共有的不饱和内酯。拟议研究的长期目标是开发治疗结核病的新疗法。对天然产物的合成研究将使实现这一目标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的内容。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未知的天然产物的作用机制。结果这些研究可以揭示结核病治疗的新范例。 公共卫生相关性：结核病 (TB) 是一种毁灭性疾病，每年在全球造成超过 100 万人死亡，但 40 多年来尚未将新的结核病特异性药物引入临床实践。开发新的结核病治疗方案，因此符合公共卫生利益。