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

项目摘要 天然产品继续对我们理解和治疗疾病的方式产生不成比例的影响。这些 生物预先验证的治疗线索已经启发了FDA批准的药物的50%，这一事实突显了 研究细胞培养中具有独特活性的生物化学类型的重要性。受到丰富机遇的启发 对于化学、生物和医学交界处的天然产品，这项建议侧重于一系列 具有稠合的[5-8-5]碳环分子骨架的萜类化合物。这个家族的旗舰成员 拥有有效的，尽管不同的药理学特征。例如，褐霉素A稳定14-3-3蛋白- 蛋白质相互作用(PPI)，麦芽球蛋白A是一种细胞毒性的膜干扰物，而双极化内酯A抑制HMG-CoA 还原酶。这些萜类化合物对其不同生物受体的特异性由其同一性决定 以及围绕共同的5-8-5亚结构的取代基的排列。给出了复杂的构象 关于环辛烷的动力学，我们假设中心八元环两侧的基团调节 整体分子形状。这一潜在的可编程特征可能允许这个萜类家族与 不同的生物受体。因此，[5-8-5]环系统似乎是设计的特权脚手架 新的治疗方法。然而，现有的对这类萜类化合物的研究方法依赖于收敛的、靶向性的。 化学反应。从药物发现的角度来看，缺乏使[5-8-5]基序多样化的化学物质是 主要障碍是理解和推进这一天然产物家族的药理作用。 在过去的资助期间，我们开发了一个合成平台来准备和编辑棕霉素支架。 我们现在寻求在几个方向上扩展这种化学。在目标1中，我们将利用我们的平台建立 对单个14-3-3个PPI给予选择性的褐霉素A的特性。在这样做的时候，我们带来了一种独特的化学物质 对长期存在的选择性调节14-3-3相互作用组的问题的看法。在目标2中，我们将 扩展我们的合成策略以捕获麦冬糖苷A和双极化内酯A。这些异构体的二十七烯具有 对5-8-5支架的外围和骨架修饰，这是现有化学方法无法解决的。我们 勾勒出从常见的5-8-5中间体到这些分子的使能合成入口点。因此，成功了 拟议研究的完成将建立一个不同的平台来重新设计[5-8-5]萜类化合物 化学类型。它还将确定是否可以利用融合蛋白来询问特定的组件 细胞培养中的14-3-3互作组。这项研究将大大拓宽获得[5-8-5]天然萜类化合物的途径 具有不同药理特性的产品，并阐明了如何在化学上进化这种化学类型 特定的功能端点。

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.