摘要
Combretastatin A-4(CA-4)是一个天然的秋水仙碱结合位点的微管蛋白抑制剂,具有抗肿瘤活性。PI3K信号通路是细胞内重要的信号转导通路之一,也是癌细胞中常见的异常表达信号通路。微管蛋白抑制剂和信号通路激酶抑制剂均为抗肿瘤药物研发的热点。设计、筛选并合成了具有秋水仙碱和PI3K双靶点的CA-4衍生物。利用SBDD技术,采用活性基团协作的方法,对CA-4进行秋水仙碱和PI3K双靶点结构改造。结合CA-4的构效关系,保留A环及3个甲氧基,以羰基取代连接双键碳以保证顺式构型,苯并呋喃环取代B环,B环侧链引入卤素增效,依据结合活性自由能打分值筛选出9种靶点活性高的衍生物进行分子对接分析及可视化分析,并通过碘代、溴代、Rap-Stoermer偶联反应和Heck偶联反应合成目标化合物CA-4,其结构经1 H NMR、13 C NMR和MS确证。活性测试结果表明:目标化合物对乳腺癌MCF-7和MDA-MB-2312种肿瘤细胞具有抑制作用。
Combretastatin A-4(CA-4)is a natural tubulin inhibitor that binds to colchicine sites and has anti-tumor activity.PI3K signaling pathway is one of the important intracellular signaling pathways and a common abnormal expression signaling pathway in cancer cells.Nowadays,tubulin inhibitors and signal pathway kinase inhibitors are both hot topics in the research and development of anti-tumor drugs.CA-4 derivatives with dual targets of colchicine and PI3K were designed,screened and synthesized.Using the SBDD technology and the active group cooperation method,CA-4 was modified by colchicine and PI3K dual-target structure.Based on the CA-4 structure-activity relationship,the A-ring and three methoxy groups were retained,and the carbonyl group was substituted for the connecting double bond carbon to ensure the cis-configuration.The benzofuran ring replaced the B-ring,and the B-ring side chain was enhanced by introducing halogen.Nine derivatives with high target activity were screened based on the binding activity free energy score for molecular docking analysis and visualization.They were synthesized through iodine,bromination,Rap-Stoermer coupling reactions,and Heck coupling reactions,and their structures were confirmed by 1 H NMR,13 C NMR and MS.The activity test results showed that the target compounds had inhibitory effects on two kinds breast cancer tumor cells,MCF-7 and MDA-MB-231.
作者
高祎婷
丁茂鹏
马腾
周昊天
刘晓航
孙晓飞
马成
GAO Yiting;DING Maopeng;MA Teng;ZHOU Haotian;LIU Xiaohang;SUN Xiaofei;MA Cheng(School of Pharmacy,Xinjiang Second Medical College,Karamay 834000,China;Department of physical education,Xinjiang Second Medical College,Karamay 834000,China;School of Pharmacy,Xinjiang Medical University,Urumqi 830000,China)
出处
《合成化学》
CAS
2023年第10期749-760,共12页
Chinese Journal of Synthetic Chemistry
基金
新疆维吾尔自治区自然科学基金地州科学基金资助项目(2021D01F40)
新疆第二医学院科研基金面上项目(MS202301)。
