Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.
Yantai Valiant Pharmaceutical Co. Ltd, Shandong, China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1870-1883. doi: 10.1080/14756366.2022.2096020.
Sinomenine, a morphinane-type isoquinoline-derived alkaloid, was first isolated from stems and roots of (Miq.) in 1920. Later discovery by researchers confirmed various essential biological efficacy sinomenine exerted and . In this study, a series of 15 sinomenine/furoxan hybrid compounds were designed and synthesised in search of a TNBC drug candidate. Some of the target compounds exhibited strong antiproliferative activities against cancer cell lines, especially for TNBC cells, compared to positive controls. Among them, hybrid exerted superior cytotoxic effects on cancer cell lines with exceptionally low IC (0.82 μM) against MDA-MB-231 cells with the highest safety index score. Further studies in mechanism displayed that could induce an S phase cell cycle arrest, stimulate apoptosis in MDA-MB-231 cells, disrupt mitochondrial membrane potential and exert a genotoxic effect on DNA in cancer cells. In addition, also notably inhibited MDA-MB-231 cells in both migration, invasion and adhesion.
青藤碱是一种吗啡烷型异喹啉衍生生物碱，于 1920 年首次从 （Miq.）的茎和根中分离得到。后来的研究人员的发现进一步证实了青藤碱所具有的多种重要的生物功效，包括抗炎和镇痛。在本研究中，设计并合成了一系列 15 种青藤碱/偕二氮杂戊烷杂合化合物，以期寻找一种治疗三阴性乳腺癌的药物候选物。与阳性对照相比，部分目标化合物对癌细胞系表现出较强的抗增殖活性，尤其是对三阴性乳腺癌细胞。其中，杂合化合物 对 MDA-MB-231 细胞的细胞毒性作用最强，IC （0.82 μM）最低，安全指数评分最高。进一步的机制研究表明， 可诱导 S 期细胞周期停滞，刺激 MDA-MB-231 细胞凋亡，破坏线粒体膜电位，并对癌细胞的 DNA 产生遗传毒性作用。此外， 还显著抑制了 MDA-MB-231 细胞的迁移、侵袭和黏附。
