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.

本计划项目资助申请的组合化学部分（项目1）的总体目标是使用固相和溶液相组合合成以及相切换方法演示基于机制的抗癌药物发现的新策略。先导化合物结构鉴定主要来源于天然产物和基于靶点的阵列设计。高质量的，确定的化合物库将提供合理的铅优化所需的广泛的结构-活性关系。具体而言，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CA的聚焦文库。基于合理设计和人Cdc 25 B与肽配体的共晶体的200个肽模拟物，2. 新的磷酸基团模拟物的设计，其目标是鉴定用于高选择性蛋白磷酸酶抑制剂的新支架，3. 准备一个CA库。femtomolar抗有丝分裂剂tubulysin A的500个类似物，目标是开发靶向微管组装的选择性抗癌剂，4. 探索新的合成方法，用于制备和分析新的动态文库， 磷酸酶抑制和新类型的抗增殖剂的发现。拟议的计划代表了多方面的努力，以改善目前的方法， 有机分子的组合合成，建立新的策略，使用天然产物作为药物发现的先导结构，并确定新的机制为基础的抗癌剂。