STUDIES OF TUBULIN-INTERACTIVE ANTICANCER DRUGS

微管蛋白相互作用抗癌药物的研究

• 批准号: 6821124
• 负责人: DAVID GEORGE IAN KINGSTON
• 金额: $ 32.09万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821124
• 关键词: active sites; affinity labeling; analog; antineoplastics; binding sites; biological products; biomimetics; biotechnology; chemical binding; chemical models; chemical synthesis; conformation; drug design /synthesis /production; drug interactions; drug receptors; drug screening /evaluation; epothilon; fluorescence resonance energy transfer; fluorescence spectrometry; fluorescent dye /probe; nuclear magnetic resonance spectroscopy; paclitaxel; polymerization; receptor binding; tubulin

DESCRIPTION (provided by applicant): The natural product paclitaxel (Taxol/R) is one of the most important currently available anticancer drugs. Its primary mechanism of action is to bind to polymerized tubulin and stabilize it, thus interfering with the mammalian cell cycle and triggering programmed cell death, or apoptosis. Three other natural products or groups of natural products, the epothilones, discodermolide, and eleutherobin and related compounds such as sarcodictyin, have all been found to act by essentially the same mechanism, even though they have very different chemical structures. The fundamental hypothesis of the proposed work is that the four compound classes mentioned above bind to tubulin in microtubules in similar but yet different ways, and that an understanding of the binding mode of each compound class will enable the design and synthesis of simplified compounds that bind as well as the natural products. The work proposed is divided into three related but distinct parts. . Modeling and synthesis of simplified analogs of paclitaxel, based on synthetic, biophysical, rotational-echo double-resonance/REDOR NMR, and modeling studies that point to one particular structure as the constrained paclitaxel conformer that best mimics paclitaxel's tubulin-bound conformation. . Modeling, synthetic, biophysical, and REDOR NMR studies of the epothilones, discodermolide, and eleutherobin that will lead to a rigorous definition of the tubulin-binding conformations and modes of these compounds. . Synthesis of constrained analogs of the epothilones, discodermolide, and eleutherobin that mimic the binding conformations elucidated in the second part. The ultimate goal of the work is to design, synthesize, and evaluate simplified analogs of paclitaxel, the epothilones, discodermolide, and eleutherobin, which will bind effectively to polymerized tubulin. Such compounds are expected to show good tubulin polymerization and cytotoxic properties, and may thus become synthetically accessible anticancer agents.

描述（由申请人提供）：天然产品紫杉醇（紫杉醇/R）是当前最重要的抗癌药物之一。它的主要作用机理是结合聚合小管蛋白并稳定它，从而干扰哺乳动物细胞周期并触发程序性细胞死亡或凋亡。其他三种天然产物或天然产物组，即雌酮，dincodermolide和eletearobin及其相关化合物，例如肌动蛋白蛋白，都被发现它们具有基本相同的机制，即使它们具有非常不同的化学结构。 所提出的工作的基本假设是，上述四个化合物类别以相似但不同的方式与微管中的微管蛋白结合，并且对每个化合物类别的结合模式的理解将促进与自然产物以及自然产物和天然产物结合的简化化合物的设计和合成。提出的工作分为三个相关但不同的部分。 。基于合成，生物物理，旋转回波双回应/重新旋转NMR的简化类似物的建模和合成，以及建模研究，将一种特定的结构作为约束的紫杉醇构象异构体，最佳模拟了帕克列赛的Tubulinaxel的tubulin-ind-in-indimimics conformation。 。对这些化合物的小管蛋白结合构象和模式的严格定义，对卵黄酮，dinder甲和雌激素的建模，合成，生物物理和重新NMR研究。 。在第二部分中阐明的结合构象的结合构象的结合构成的结合构成。 这项工作的最终目的是设计，合成和评估紫杉醇，肩hose酮，dosodermolide和Eleteuthelobin的简化类似物，这些类似物将有效地与聚合微管蛋白结合。这种化合物有望显示出良好的微管蛋白聚合和细胞毒性特性，因此可能会成为合成的抗癌剂。