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.

项目概要天然产物仍然是新先导化合物发现的最重要来源之一的药剂。它们占据了化学空间的广阔区域，提供了更大的多样性与经典药物分子相比的结构及其生物学特性。强效来自大自然的化合物为开发新化学品提供了重要的建筑灵感疗法，超过 80% 的所有药物和超过 65% 的抗癌药物均源自、源自或受其启发天然产品；然而，它们的结构复杂性和有限的可用性往往是唯一的障碍阻碍了他们的进一步研究和临床开发。作为位于界面的合成有机化学家化学和生物学，我们的研究计划致力于以以下形式提供这一供应问题的解决方案复杂的生物活性天然产物的可持续和实用合成，并执行他们的化学生物学的基础研究。通过开发新的合成策略以及针对特定目标的方法论，我们打算提供有效获取复杂生物活性天然产品的途径，并将其带入药物化学领域。具体来说，在这个提案中，我们描述了几种合成方法多种萜类天然产物类别：异马拉巴烷三萜、印苦内酯和多种全氢苯并[e]茚基萜类化合物。我们已经建立了对所有四个具有挑战性的立体发散访问自然界中罕见的 6/6/5 三环萜类核心结构的立体异构体。而且，我们最近使用允许快速多样化的合成蓝图完成了几种异马拉烷。我们是开始从事生物学研究，我们与化学生物学专家的持续合作将提供了测试这些化合物及其类似物的治疗活性的绝佳机会，以及阐明其作用机制、分子靶点和代谢物。预计这些研究将为抗癌和抗感染药物提供前所未有的分子拓扑和功能，以及增进我们对某些癌症和致病性疾病的机制特异性的基本了解。