COMBINATORIAL SYNTHESIS OF ANTICANCER LIBRARIES

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理的抗癌药物发现的新策略。铅结构识别主要来源于天然产物和靶基阵列设计。高质量的已定义化合物文库将提供合理的铅优化所需的广泛的结构-活性关系。具体地说，我们有四个主要的战略目标：1.基于合理的设计和人的cdc25b与一种多肽配体的共晶，开发出用于制备约200肽模拟物的溶液相和固相并行合成方案；2.设计新型的磷酸基团模拟物，目的是为高选择性的蛋白磷酸酶抑制剂寻找新的支架；3.准备一个约500个类似物的微管分子抗癌剂Tubuysin a的库，目标是开发靶向微管组装的选择性抗癌药物；4.探索新的合成方法，用于制备和分析新的动态文库 磷酸酶抑制和新型抗增殖剂的发现。拟议的计划代表了一项多层面的努力，以改进目前的方法，以 有机分子的组合合成，建立利用天然产物作为药物发现的先导结构的新策略，并确定新的基于机制的抗癌药物。

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.