Synthesis of Biologically Active Terpenoids

生物活性萜类化合物的合成

基本信息

批准号：
10587602
负责人：
David Sarlah
金额：
$ 37.1万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587602
关键词：
Acceleration Adverse effects Affect Anti-Infective Agents Antineoplastic Agents Architecture Biological Biological Testing Biology Breathing Cancer cell line Cessation of life Chemical Engineering Chemical Structure Chemicals Chemistry Collaborations Communicable Diseases Complex Creativeness Cyclization Development Disease Evaluation Excision Goals Human Indenes Investigation Isomerism Knowledge Lead Malignant Neoplasms Medicine Metabolic Metastatic/Recurrent Methodology Methods Molecular Molecular Mechanisms of Action Molecular Probes Molecular Target Mutation Natural Products Nature Neoplasm Metastasis Oncogenes Oncology Operative Surgical Procedures Organic Synthesis Organism Outcome Pathogenicity Patients Periodicity Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Polyenes Preparation Primary Neoplasm Prodrugs Property Radiation therapy Rationalization Reactive Inhibition Research Resistance Role Signal Pathway Signal Transduction Source Specificity Stereoisomer Structure Terpenes Testing Therapeutic Toxic effect Toxicology Work analog anti-cancer anticancer activity bioactive natural products cancer therapy carcinogenicity chemical synthesis clinical development cytotoxic driving force drug development effective therapy fighting flexibility infectious disease treatment metabolic profile molecular targeted therapies natural product inspired novel novel strategies pathogen prevent programs scaffold small molecule standard of care tool tumor

项目摘要

PROJECT SUMMARY Natural products continue to be one of the most important sources of new lead compounds for the discovery of medicinal agents. They occupy vast regions of chemical space, providing much greater diversity in their structures as well as their biological properties compared to those of classical drug molecules. Potent compounds from nature have provided paramount architectural inspiration for developing new chemical therapies, with more than 80% of all drugs and over 65% of anticancer drugs being, derived from, or inspired by natural products; however, their structural complexity and limited availability are often the sole obstacles preventing their further study and clinical development. As synthetic organic chemists situated at the interface of chemistry and biology, our research program is devoted to providing solutions to this supply problem in the form of sustainable and practical syntheses of complex biologically active natural products, and to performing fundamental studies of their chemical biology. By developing new synthetic strategies, as well as target-specific methodologies, we intend to provide efficient access to complex bioactive natural products and bring them within the realm of medicinal chemistry. Specifically, in this proposal we describe synthetic approaches to several diverse terpenoid natural product classes: isomalabaricane triterpenoids, nimbolide, and a vast range of perhydrobenz[e]indene-based terpenoids. We already established stereodivergent access to all four challenging stereoisomers of the rare 6/6/5 tricyclic terpenoid core structure that occurs in nature. Moreover, we recently completed several isomalabaricanes, using synthetic blueprint that permits rapid diversification. We are beginning to engage in biological investigations, and our ongoing collaboration with chemical biology experts will provide an excellent opportunity to test these compounds and their analogues for therapeutic activities, as well as to elucidate their mechanisms of action, molecular targets, and metabolites. It is expected that these studies will provide anticancer and anti-infective agents with unprecedented molecular topologies and functions, as well as advance our basic knowledge of their mechanistic specificity for certain cancers and pathogenic diseases.

项目摘要天然产品仍然是发现新铅化合物的最重要来源之一药剂。他们占据了巨大的化学空间区域，为其提供了更大的多样性与经典药物分子相比，结构及其生物学特性。有效来自自然的化合物为开发新化学化学提供了最重要的建筑灵感所有药物中有80％以上的疗法和超过65％的抗癌药物源自或源自天然产品；但是，它们的结构复杂性和有限的可用性通常是唯一的障碍防止他们进一步的研究和临床发展。作为合成有机化学家位于化学和生物学，我们的研究计划致力于以形式提供解决此供应问题的解决方案复杂生物活性天然产品的可持续和实用合成，并执行对其化学生物学的基本研究。通过制定新的合成策略以及特定于目标的方法论，我们打算为复杂的生物活性天然产品提供有效的访问权限，并将其带入药物化学领域。具体而言，在此提案中，我们描述了几种的合成方法多样的萜类自然产品类别：异丙烷三萜类，Nimbolide和大量范围 hydrobenz [e]基于印度的萜类化合物。我们已经建立了对所有四个挑战的立体访问权限罕见的6/6/5三环萜类核心结构的立体异构体发生在自然界中。而且，我们最近使用允许快速多样化的合成蓝图完成了几个异构体。我们是开始进行生物学研究，我们与化学生物学专家进行的持续合作将提供了一个绝佳的机会来测试这些化合物及其类似物的治疗活动为了阐明其作用机理，分子靶标和代谢物。预计这些研究还将为抗癌和抗感染剂提供前所未有的分子拓扑和功能随着我们对某些癌症和致病性疾病的机械特异性的基本知识。