Merocytochalasans, Photocytochalasans and the Optical Control of the Actin Cytoskeleton

细胞松弛素、光细胞松弛素和肌动蛋白细胞骨架的光学控制

• 批准号: 9920728
• 负责人: DIRK HARTWIG TRAUNER
• 金额: $ 26.57万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920728
• 关键词: Actins; Affinity; Biological Availability; Biology; Biomimetics; Cells; Cellular biology; Chemistry; Complex; Coupling; Cyclodepsipeptides; Cytochalasins; Cytoskeleton; Family; Family member; Foundations; Goals; Life; Light; Malignant Neoplasms; Molecular; Molecular Structure; Natural Products; Optics; Pyrogallol; Reaction; Role; Structure; Structure-Activity Relationship; Ursidae Family; Work; analog; base; cancer cell; cell type; cytotoxicity; design; experience; fascinate; irradiation; jasplakinolide; programs; tool; virtual

Merocytochalasans, Photocytochalasans, and the Optical Control of the Actin Cytoskeleton Project Summary/Abstract The goal of this project is to synthesize and study cytochalasans with new structural and functional features. Cytochalasans generally target the actin cytoskeleton and account for some of the most potent natural products known. New members of this family that combine fascinating molecular structures with interesting bioactivities, such as the merocytochalasans, continue to emerge. We propose to synthesize these compounds and evaluate them in depth for their effect on the actin cytoskeleton. To this end, we will develop biomimetic cascade reactions that are based on the largely unexplored oxidative coupling chemistry of pyrogallols. In parallel, we will design and synthesize cytochalasans that bear photoswitches and can be reversibly activated with light. These “photocytochalasans” change their affinity, efficacy, or bioavailability upon irradiation and allow for the precision control of actin dynamics. We will extend our program on the optical control of the actin cytoskeleton to photoswitchable derivatives of the jasplakinolides. To support our claims, we provide preliminary results that demonstrate that the photopharmacology of the actin cytoskeleton is indeed viable.

细胞松弛素、光细胞松弛素和肌动蛋白细胞骨架的光学控制 项目概要/摘要 该项目的目标是合成和研究具有新结构和功能特征的细胞松弛聚糖。 细胞松弛素通常以肌动蛋白细胞骨架为目标，并产生一些最有效的天然产物 已知。这个家族的新成员将迷人的分子结构与有趣的生物活性结合在一起， 例如merocytochalasans，不断出现。我们建议合成这些化合物并评估 深入研究它们对肌动蛋白细胞骨架的影响。为此，我们将开发仿生级联反应 它们基于很大程度上未经探索的连苯三酚氧化偶联化学。同时，我们将设计 并合成带有光开关并且可以被光可逆激活的细胞松弛聚糖。这些 “光细胞松弛素”在照射后会改变其亲和力、功效或生物利用度，并允许精确度 肌动蛋白动力学的控制。我们将把肌动蛋白细胞骨架的光学控制项目扩展到 jasplakinolides 的光可切换衍生物。为了支持我们的主张，我们提供了初步结果 证明肌动蛋白细胞骨架的光药理学确实可行。