Wu Lichuan, Wang Guizhen, Liu Shuaibing, Wei Jinrui, Zhang Sen, Li Ming, Zhou Guangbiao, Wang Lisheng
School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004, PR China.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Sci Rep. 2016 Oct 27;6:35918. doi: 10.1038/srep35918.
Matrine, an active component of root extracts from Sophora flavescens Ait, is the main chemical ingredient of Fufang Kushen injection which was approved by Chinese FDA (CFDA) in 1995 as an anticancer drug to treat non-small cell lung cancer and liver cancer in combination with other anticancer drugs. Owning to its druggable potential, matrine is considered as an ideal lead compound for modification. We delineate herein the synthesis and anticancer effects of 17 matrine derivatives bearing benzo-α-pyrone structures. The results of cell viability assays indicated that most of the target compounds showed improved anticancer effects. Further studies showed that compound 5i could potently inhibit lung cancer cell proliferation in vitro and in vivo with no obvious side effects. Moreover, compound 5i could induce G1 cell cycle arrest and autophagy in lung cancer cells through up-regulating P27, down-regulating CDK4 and cyclinD1 and attenuating PI3K/Akt/mTOR pathway. Suppression of autophagy attenuated 5i induced proliferation inhibition. Collectively, our results infer that matrine derivative 5i bears therapeutic potentials for lung cancer.
苦参碱是苦参根提取物的一种活性成分，是复方苦参注射液的主要化学成分。该注射液于1995年被中国食品药品监督管理总局（CFDA）批准为抗癌药物，可与其他抗癌药物联合用于治疗非小细胞肺癌和肝癌。由于其具有成药潜力，苦参碱被认为是一种理想的可用于修饰的先导化合物。在此，我们阐述了17种具有苯并-α-吡喃酮结构的苦参碱衍生物的合成及其抗癌作用。细胞活力测定结果表明，大多数目标化合物显示出增强的抗癌作用。进一步研究表明，化合物5i在体外和体内均能有效抑制肺癌细胞增殖，且无明显副作用。此外，化合物5i可通过上调P27、下调CDK4和细胞周期蛋白D1以及减弱PI3K/Akt/mTOR信号通路，诱导肺癌细胞发生G1期细胞周期阻滞和自噬。抑制自噬可减弱5i诱导的增殖抑制作用。总体而言，我们的结果表明苦参碱衍生物5i具有治疗肺癌的潜力。
