A Divergent Platform to Chemically Redesign Bioactive 5-8-5 Terpenoids

项目摘要 天然产品继续对我们如何理解和治疗疾病产生不成比例的影响。这些 生物学预先验证的治疗药物已经激发了约50%的FDA批准的药物，这一事实强调了 在细胞培养中研究具有独特活性的生物化学型的重要性。受丰富机会的启发， 对于处于化学、生物学和医学交界面的天然产物，本建议侧重于一个家族， 以稠合的[5-8-5]碳环分子框架为特征的萜类。这个家族的旗舰成员 具有影响力，尽管不同，药理学特征。例如，梭孢菌素A稳定14-3-3蛋白- 蛋白质相互作用（PPI），蛇孢菌素A是一种细胞毒性膜破坏剂，双极性蛋白A抑制HMG-CoA 还原酶。这些萜类化合物对它们不同生物受体的特异性由它们的同一性决定。 以及取代基围绕共同的5-8-5亚结构的排列。考虑到复杂的构象 动力学的环辛烷类化合物，我们假设，侧翼的中央八元环的基团调节 整体分子形状。这种潜在的可编程特征可能允许这种萜类化合物家族与 不同的生物受体。因此，[5-8-5]环系统似乎是一个特权的支架设计， 新疗法。然而，针对该萜类化合物家族的现有方法依赖于会聚的、靶向特异性的、非靶向的。 化学.从药物发现的透镜来看，缺乏使[5-8-5]基序多样化的化学方法是药物发现的关键。 这是理解和推进这一天然产物家族药理学的主要障碍。 在过去的资助期间，我们开发了一个合成平台来制备和编辑梭孢菌素支架。 我们现在试图在几个方向上扩展这种化学反应。在目标1中，我们将利用我们的平台建立 具有对单个14-3-3 PPI具有选择性的梭孢菌素A的特征。在此过程中，我们将一种独特的化学物质 选择性调节14-3-3相互作用组的长期问题的观点。在目标2中，我们将 将我们的合成策略扩展到捕获蛇孢菌素A和双极性蛋白A。这些异构二倍半萜的特征在于 对5-8-5支架的外周和骨骼修饰不能通过现有化学处理。我们 概述了从一个共同的5-8-5中间体到这些分子的合成切入点。成功的， 完成拟议的研究将建立一个不同的平台，以化学重新设计[5-8-5]萜类化合物 化学型它还将确定是否可以利用fusicoccins来询问特定的组分， 细胞培养中的14-3-3相互作用组。这项研究将显著拓宽[5-8-5]萜类化合物的天然来源 具有不同药理学特征的产品，并阐明如何化学进化这种化学型， 一个特定的功能终点。

PROJECT ABSTRACT Natural products continue to have a disproportionate impact on how we understand and treat disease. These biologically pre-validated therapeutic leads have inspired ~50% of FDA-approved drugs, a fact underscores the importance of studying biogenic chemotypes with unique activity in cell culture. Inspired by the rich opportunities for natural products at the interface of chemistry, biology, and medicine, this proposal focuses on a family of terpenoids distinguished by a fused [5-8-5] carbocyclic molecular framework. The flagship members of this family possess impactful, albeit divergent, pharmacological profiles. For example, fusicoccin A stabilizes 14-3-3 protein- protein interactions (PPIs), ophiobolin A is a cytotoxic membrane disruptor, and bipolarolide A inhibits HMG-CoA reductase. The specificity of these terpenoids for their diverse biological receptors is determined by the identity and arrangement of substituents surrounding a common 5-8-5 substructure. Given the complex conformational dynamics of cyclooctanoids, we postulate that the groups flanking the central eight-membered ring modulate the overall molecular shape. This potentially programmable feature might allow this terpenoid family to interface with diverse biological receptors. Thus, the [5-8-5] ring system appears to be a privileged scaffold for the design of novel therapeutics. However, existing approaches to this family of terpenoids rely on convergent, target-specific chemistry. Viewed through the lens of drug discovery, the lack of chemistry to diversify the [5-8-5] motif is the main impediment to understanding and advancing the pharmacology of this natural product family. During the past grant period, we developed a synthetic platform to prepare and edit the fusicoccin scaffold. We now seek to extend this chemistry in several directions. In Aim 1, we will exploit our platform to establish the features of fusicoccin A that impart selectivity for individual 14-3-3 PPIs. In doing so, we bring a unique chemical perspective to the long-standing problem of selectively modulating the 14-3-3 interactome. In Aim 2, we will extend our synthetic strategy to capture ophiobolin A and bipolarolide A. These isomeric sesterterpenes feature peripheral and skeletal modifications to the 5-8-5 scaffold that cannot be addressed by existing chemistry. We outline an enabling synthetic entry point to these molecules from a common 5-8-5 intermediate. Thus, successful completion of the proposed research will establish a divergent platform to chemically redesign [5-8-5] terpenoid chemotypes. It will also establish whether the fusicoccins can be exploited to interrogate specific components of the 14-3-3 interactome in cell culture. This research will signifyingly broaden access to [5-8-5] terpenoid natural products with diverse pharmacological profiles and shed light on how to chemically evolve this chemotype toward a specific functional endpoint.