COMBINATORIAL SYNTHESIS OF ANTICANCER LIBRARIES

抗癌文库的组合合成

• 批准号: 6928830
• 负责人: Peter Wipf
• 金额: $ 18.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928830
• 关键词: antimitotics; antineoplastics; biological products; combinatorial chemistry; drug discovery /isolation; peptide analog; phosphatase inhibitor; phosphates

The overall goal of the combinatorial chemistry section (Project 1) of this Program Project grant application is the demonstration of new strategies for mechanism-based anticancer drug discovery using solid-phase and solution-phase combinatorial synthesis as well as phase-switching methods. Lead structure identification is mainly derived from natural products and target-based array design. High quality, defined-compound libraries will provide the broad structure-activity relationship necessary for rational lead optimization. Specifically, we have four major strategic goals: 1. to develop solution-phase and solid-phase parallel synthesis protocols for the preparation of a focused library of ca. 200 peptide mimetics based on rational design and the co-crystal of human Cdc25B and a peptide ligand, 2. the design of novel phosphate group mimics with the goal of identifying new scaffolds for highly selective protein phosphatase inhibitors, 3. to prepare a library of ca. 500 analogs of the femtomolar antimitotic agent tubulysin A with the goal to develop selective anticancer agents that target microtubule assembly, 4. to explore new synthetic methods for the preparation and analysis of novel dynamic libraries for phosphatase inhibition and the discovery of new classes of antiproliferative agents. The proposed program represents a multi-dimensional effort to improve current methodologies for the combinatorial synthesis of organic molecules, establish new strategies for the use of natural products as lead structures for drug discovery, and identify novel mechanism-based anticancer agents.

该计划项目拨款申请的组合化学部分（项目1）的总体目标是展示使用固相和溶液相组合合成以及相转换方法的基于机制的抗癌药物发现的新策略。先导结构识别主要来源于天然产物和基于靶点的阵列设计。高质量、明确的化合物库将提供合理先导化合物优化所需的广泛结构-活性关系。具体来说，我们有四个主要战略目标： 1. 开发溶液相和固相平行合成方案，用于制备大约的重点库。基于合理设计以及人 Cdc25B 和肽配体的共晶的 200 种肽模拟物，2. 设计新型磷酸基模拟物，目的是识别高选择性蛋白磷酸酶抑制剂的新支架，3. 准备一个库约500 种飞摩尔抗有丝分裂剂微管蛋白 A 的类似物，目标是开发针对微管组装的选择性抗癌药物，4. 探索新的合成方法，用于制备和分析新型动态文库 磷酸酶抑制和新型抗增殖剂的发现。拟议的计划代表了改进当前方法的多维努力 有机分子的组合合成，建立使用天然产物作为药物发现的先导结构的新策略，并确定基于新机制的抗癌药物。