COMBINATORIAL SYNTHESIS OF ANTICANCER LIBRARIES

本项目资助申请的组合化学部分（项目1）的总体目标是利用固相和溶液相组合合成以及相转换方法，展示基于机制的抗癌药物发现的新策略。引线结构的识别主要来源于天然产物和基于目标的阵列设计。高质量、明确的化合物库将为合理的先导优化提供广泛的构效关系。具体来说，我们有四个主要战略目标：1。基于合理设计和人Cdc25B与肽配体共晶，开发液相和固相平行合成方案，制备约200个肽类模拟物集中文库；新型磷酸基模拟物的设计目标是鉴定高选择性蛋白磷酸酶抑制剂的新支架，3。制备约500个飞摩尔抗有丝分裂药物管溶素a类似物的文库，目的是开发靶向微管组装的选择性抗癌药物；探索新的合成方法来制备和分析新的动态文库

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.