羰基钴一氧化碳释放分子（CORM）的抗肿瘤作用机制研究

一氧化碳(CO)类似于NO，是机体内一种重要的信使分子，羰基钴类一氧化碳释放分子（CORM）作为CO的前药形式，显示出良好的抗肿瘤活性。非甾体抗炎药（NSAIDs）具有化学预防和抗癌作用。本项目以探讨羰基钴一氧化碳释放分子的抗肿瘤活性机制及羰基钴CORM中CO的作用机制为研究目标，研究内容包含三个方面：一是通过对非甾体抗炎药COX-2抑制剂的结构修饰得到酯类、酰胺类、含有甾体母核和糖类的羰基钴类一氧化碳释放分子。二是通过MTT实验检测CORM和iCORM对肿瘤细胞MDA-MB231、Hela和HepG2的增殖抑制作用，以及CO荧光探针和线粒体荧光探针探索药物分子对线粒体的靶向作用，初步探明羰基钴一氧化碳释放分子中CO在抗肿瘤活性中的作用机制；三是进一步利用CO荧光探针研究CO信使分子在正常细胞LO2中的释放行为，为CO使用安全性提供理论依据，同时对CORM的毒性进行研究。

Carbon monoxide (CO), similar to NO, is an important messenger molecule in the body. As a prodrug form of CO, carbonyl cobalt carbon monoxide releasing molecule (CORM) shows good antitumor activity. It is an attractive method to develop new anticancer chemotherapy combined a metal unit with anti-inflammatory drugs. This work will focus on solving the anti-tumor activity mechanism of cobalt carbonyl monoxide releasing molecule and the role of CO in cobalt carbonyl CORM as a key scientific issue. The non-steroidal anti-inflammatory drug（COX-2 inhibitor）is used as the substrate for structural modification to obtain ester, amide functional group, steroid body and carbohydrate. The inhibitory effect of CORM and iCORM on the proliferation of LO2 cells and MDA-MB231, HeLa and HepG2 cells was detected by MTT assay. Through CO fluorescence probe and mitochondrion fluorescence probe, we will explore the targeting effect of drug molecules on mitochondrion. Combined with flow cytometry, the possible anti-tumor mechanism of carbonyl cobalt carbon monoxide releasing molecules will be explored. Through studying the acute toxicity of CORMs on the basis of the pharmacological activity and mechanism of carbon monoxide releasing molecules of carbonyl cobalt, we would hope to obtain the candidate drugs with better pharmacological activity and lower toxicity.