那可丁系列衍生物结构-代谢激活关系研究

Noscapine, a phthalideisoquinoline alkaloid isolated from.opium, has been widely used as an antitussive drug. In recent years, the antitumor activity of noscapine has drawn much attention. Noscapine is being developed as anti-tumor lead compound, and many derivatives with the core structure of noscapine appear one after another. Adverse effects of noscapine induced by its bioactivation strongly limit its clinical utilization. Therefore, it is very necessary to evaluate the bioactivation potential of noscapine derivatives when developing these derivatives as anti-tumor drugs. On the basis of previous work, the present program aims to investigate the bioactivation potential of noscapine derivatives, including evaluation of time-dependent inhibition of derivatives towards drug metabolizing enzymes and chemical trapping of reactive metabolites using reduced GSH. With these experimental data, the computer model was used to qualitatively and quantitatively predict metabolic activation-structure relationship. In combination with antitumor activity-structure relationship, it is hopeful to design an excellent noscapine derivative with efficient antitumor activity and insensitive bioactivation potential.

那可丁是临床常用止咳用药。近年来，那可丁的抗肿瘤活性备受关注，目前已经作为抗肿瘤先导化合物进行开发，以其为母核的衍生物相继问世。那可丁代谢激活诱发的临床毒副作用是限制其临床使用的一个重要原因，所以在评价那可丁类系列衍生物抗肿瘤活性的同时对其代谢激活潜能的早期筛选和评价是该类药物开发必须面对的问题。本项目在前期工作的基础上，首先采用结构改造修饰的策略获得那可丁系列衍生物，并系统评价这些衍生物代谢激活潜能（包括药物代谢酶时间依赖性抑制评价和还原性谷光甘肽（GSH）对活性中间体的捕捉）。利用得到的代谢激活实验数据，结合计算机模型构建定性和定量代谢激活-结构关系。结合那可丁抗肿瘤活性-结构关系模型，设计出兼具抗肿瘤活性和代谢激活不敏感性的新型那可丁类抗肿瘤药物。

基于抗肿瘤活性导向对那可丁进行结构改造是目前那可丁抗肿瘤开发的主要策略。本课题根据前期发现的药物代谢介导那可丁毒副作用出发，试图兼顾抗肿瘤活性和代谢致毒作用两个方面，在早期研发阶段评价那可丁衍生物代谢相关的致毒潜力。到目前为止，本课题用有机合成手段得到了溴代那可丁和氨基那可丁两个那可丁的衍生物，评价了它们的代谢行为和代谢致毒的可能性。此外，本课题还进一步建立了II相代谢酶活性表征平台和毒性代谢组学平台技术，测定了那可丁及其衍生物对II相代谢酶活性的抑制以及那可丁代谢激活致毒的内源性下游通路。在以上实验结果的基础上，通过同源模建、分子对接等计算化学手段揭示影响该类化合物代谢毒性的关键结构域，为那可丁类药物的抗肿瘤开发奠定了实验数据和理论基础。截至目前为止，本课题已经圆满完成了课题任务书中的各项研究内容，科研工作量已经大大超过原计划任务。本项目共发表SCI16篇，培养博士研究生1名，硕士研究生2名,正在培养硕士研究生1名 。