Multidisciplinary Investigation of Antitubulin Heterocycles using Synthesis, Biology, and Structural Analysis

微管蛋白是一种参与微管功能的蛋白质，包括有丝分裂、细胞形态、迁移、 和细胞器的运动。微管蛋白抑制剂用于癌症治疗；然而， 目前的抑制剂往往是复杂的分子，并遭受毒性问题，多药 耐药性、低溶解性和/或缺乏对多种癌症的疗效。总体目标和长远目标 这一建议的目的是利用假说驱动的合理药物设计来开发新型杂环化合物 微管蛋白聚合抑制剂。 与本科生一起使用强大的、跨学科的指导研究计划 研究人员，我们之前开发了PY-407-C，一种含有呋喃酮的分子 阻止微管蛋白聚合，对癌细胞具有纳摩尔毒性。我们的3个独立的 但互补的目标如下所示。首先，我们将描述之前确定的PY 分子模型用于(A)微管蛋白结合，(B)抑制所需浓度 微管蛋白聚合与已知抑制剂的比较，以及(C)与非微管蛋白结合。 以评估其特异性。第二，我们将采用合理的药物设计来确定新的 通过假说驱动的多学科理性药物设计循环开发杂环微管蛋白抑制剂 (1)建模，(2)我们将设计和合成新的基于呋喃酮的目标，以及 (3)测定产物的细胞毒性。生物结果将推动新的 要模拟的合成目标，循环将重复。这一目标是创新的，因为 涉及2个不同主要本科院校的3个实验室的多PI建议 (PUIS)将汇集不同领域的专业知识来设计微管蛋白抑制剂。此外， 这些途径和方法中的许多在PUI中都特别具有创新性。第三，我们将申请 并开发模块化合成方法，使设计的抗微管蛋白杂环成为可能 通过两个并行的综合策略：(1)应用和扩展我们已发表的工作，同时 (2)研究使用C-H激活的创新策略，从而显著提高 资源效率和潜在地扩展可用于模拟的替代模式 合成(包括NH吲哚衍生物)。值得注意的是，所有目标都是独立的，就像目标2一样 使用在Aim 3或我们之前发表的合成路线中合成的化合物进行。 总体而言，我们将进行基础研究，以改进抗癌药物，同时培训下一步 一代科学家。

Tubulin is a protein involved in microtubule function, including mitosis, cell shape, migration, and movement of organelles. Tubulin inhibitors are used in cancer treatments; however, the current inhibitors tend to be complex molecules, and suffer from toxicity issues, multi-drug resistance, low solubility, and/or the lack of multi-cancer efficacy. The overall and long-term goal of this proposal is to use hypothesis-driven rational drug design to develop novel heterocyclic tubulin polymerization inhibitors. Using a robust, interdisciplinary mentoring research program with undergraduate researchers, we previously developed PY-407-C, a furanone-containing molecule that prevented tubulin polymerization and had nanomolar toxicity on cancer cells. Our 3 independent but complementary goals are as follows. First, we will characterize previously identified PY molecules for (a) tubulin binding by molecular modeling, (b) concentration needed to inhibit tubulin polymerization compared to known inhibitors, and (c) binding to non-tubulin proteins in order to assess specificity. Second, we will employ rational drug design to identify new heterocyclic tubulin inhibitors via a hypothesis-driven, multi-disciplinary rational drug design loop of (1) modeling, (2) from which we will design and synthesize new furanone-based targets, and (3) assay the resultant compounds for cytotoxicity. Biological results will then drive new synthetic targets to be modeled, and the loop will be repeated. This aim is innovative in that a multi-PI proposal involving the work of 3 labs at 2 different primarily undergraduate institutions (PUIs) will bring together different areas of expertise to tubulin inhibitor design. Furthermore, many of these approaches and methods are particularly innovative at a PUI. Third, we will apply and develop modular synthetic methods that give access to designed anti-tubulin heterocycles through two parallel synthetic strategies by: (1) applying and extending our published work while (2) investigating innovative strategies that employ C-H activation, thus significantly improving resource efficiency and potentially extending the substitution patterns available for analogue synthesis (including NH indole derivatives). Of note, all aims are independent as aim 2 can be performed with compounds made in aim 3 or by our previously published synthetic routes. Overall, we will perform basic research to improve anticancer agents while training the next generation of scientists.