Synthesis of Biologically Active Terpenoids

项目摘要 天然产物仍然是发现新先导化合物的最重要来源之一 药物制剂。它们占据了化学空间的广阔区域，在它们的化学结构中提供了更大的多样性。 结构以及它们的生物学性质与经典药物分子的那些相比。强效 来自自然界的化合物为开发新的化学物质提供了最重要的建筑灵感， 超过80%的药物和超过65%的抗癌药物是，来自或启发于 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 阻止了它们的进一步研究和临床开发。作为有机合成化学家， 化学和生物学，我们的研究计划致力于提供这种形式的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的合成，并执行 化学生物学的基础研究。通过开发新的合成策略，以及目标特异性 方法，我们打算提供有效的获取复杂的生物活性天然产品，并将其纳入 药物化学领域具体而言，在本提案中，我们描述了几种合成方法， 不同的萜类天然产物类别：isomalabaricane三萜类，印楝内酯，和广泛的 基于全氢苯并[e]茚的萜类化合物。我们已经建立了立体分散访问所有四个挑战 天然存在的罕见6/6/5三环萜类核心结构的立体异构体。此外，我们最近 完成了几个isomalabaricanes，使用合成蓝图，允许快速多样化。我们 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 也提供了测试这些化合物及其类似物的治疗活性的极好机会， 以阐明其作用机制、分子靶点和代谢物。预计这些研究 将提供具有前所未有的分子拓扑结构和功能的抗癌和抗感染剂， 作为推进我们对它们对某些癌症和致病性疾病的机制特异性的基本知识。

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.