基于结构生物学的Taccalonolide AN 衍生物的设计、合成及抗肿瘤活性研究

Antibody-drug conjugates (ADCs) is a novel targeted drug, which is obtained by chemical method coupling potent chemical compound with antibody. It combines the specificity of the antibody and high efficiency of chemical drug, which has been the latest development of tumor targeted drugs. Taccalonolides are a steroid family of discovered from Taccaece which can inhibit polymerization of　microtubules, and some exhibit extremely high antitumor activity (IC50 ﹤1nM), thereby can be modified as the new "warhead drugs". In our previous work, we resolved the crystal structure ofTaccalonolide AJ-tubulin complex, and revealed its mechanism of molecular pharmacology，then summarized the key structure-activity relationship of Taccalonolides. Based on the information of structural biology, following the requirements of "warhead drug", our final goal of this project is to design and synthesize a series of Taccalonolide derivatives, and make a study of their anti-tumor effect to screen out novel Taccalonolide derivatives which show high antimor activity and stability. Then making novel conjugates by coupling Taccalonolide derivatives with anti-HER2 antibody, and to study antitumor activity of these ADCs. Finally we expect to get novel "warhead drugs" which have independent intellectual property rights and lay a foundation for the development of ADC drugs.

抗体-药物偶联物（Antibody-drug conjugates, ADC）是将强效的化学药物（弹头）与抗体通过化学方法偶联得到的新一代靶向药物，充分发挥了抗体的靶向性与化学药物的高效性。Taccalonolides是源于箭根薯科植物的一类甾体化合物，其中一些为强烈的微管抑制剂（IC50﹤1nM），有成为新型ADC “弹头”的潜力。前期研究中，我们解析了Taccalonolide AJ -微管的晶体结构，揭示了其分子药理学机制，总结了Taccalonolide的构效关系。基于结构生物学的指导，本项目拟按照“弹头”的要求, 以Taccalonolide AN为起始原料，设计、合成一系列Taccalonolide AN衍生物，筛选活性高和稳定性好的候选分子，再与抗HER2抗体偶联，进行抗肿瘤药理学和药效学研究，期望获得自主知识产权的新型“弹头”，为ADC药物的研发奠定基础。

许多抗肿瘤药物均源自天然产物的深入挖掘。基于强细胞毒性化合物（弹头）的抗体药物偶联物（ADC）是当前抗肿瘤药物研发中的热点，开发新型弹头是ADC药物研究的重要内容。箭根酮内酯是源于箭根薯和裂果薯中的抗肿瘤天然甾体化合物，靶向微管蛋白紫杉醇位点，具有稳定微管的作用。本项目在前期结构生物学研究的基础上开展了针对箭根酮内酯的结构修饰和抗体偶联化学研究。我们从裂果薯的根茎（中药水田七）中提取了其主成分箭根酮内酯A，然后以此为起始原料进行了多系列的半合成构效关系研究，主要包括C22-C23烯烃的环氧化、C2-C3环氧的氯醇化和酯化和C6羰基的还原和酯化等，最终获得了抗肿瘤活性达皮摩尔级的箭根酮内酯类似物，为箭根酮内酯的构效关系研究及其ADC药物的研发奠定了基础。