摘要
目的设计合成1-[6-(2-甲氧基苯基)-哒嗪-3-基]-N-取代哌啶-3-甲酰胺衍生物,并测定其体外抗肿瘤活性。方法以3.6-二氯哒嗪为起始原料,经取代、水解、Suzuki偶联反应得到关键中间体1-[6-(2-甲氧基苯基)-哒嗪-3-基]哌啶-3-甲酸(6),6与不同取代胺发生N-酰基化反应得到目标化合物。采用MTT法测试目标化合物对HepG2、MCF7、MDA-MB-231肿瘤细胞的抑制活性,同时评价其对人正常肝细胞LO2的细胞毒性。结果与结论共合成了10个未见文献报道的新化合物B01~B10,其结构均经ESI-MS、^(1)H-NMR和^(13)C-NMR谱确证。MTT测试结果显示,改变酰胺键的方向,化合物的活性显著下降,这说明酰胺键方向对化合物的活性具有重要影响。此外,化合物B09的活性较好[HepG2:IC_(50)=(10.07±0.50)μmol·L^(-1)],且在40μmol·L^(-1)浓度下对正常细胞无明显毒性。
To obtain a novel class of JMJD6 inhibitors,ten 1-(6-(2-methoxyphenyl)-pyridazin-3-yl)-Nsubstituted piperidine-3-carboxamide derivatives were designed and synthesized,and their in vitro antitumor activity was determined.Starting from 3,6-dichloropyridazine,the key intermediate 1-(6-(2methoxyphenyl)-pyridazin-3-yl)piperidine-3-carboxylic acid(6)was prepared via substitution,hydrolysis,and Suzuki reaction.Subsequent N-acylation of intermediate 6 with various substituted amines afforded ten target compounds(B01-B10),which have not been reported in the literature,and their structures were confirmed by ESI-MS,^(1)H-NMR,and^(13)C-NMR spectra.The MTT assay was employed to assess the inhibitory activity of the target compounds against HepG2,MCF7,and MDA-MB-231 tumor cell lines,as well as their cytotoxicity toward the normal human liver cell line LO2.The results showed that compound B09 exhibited the most potent activity(HepG2:IC_(50)=(10.07±0.50)μmol·L^(-1))and no significant cytotoxicity toward normal cells at 40 pmol·L^(-1).These findings indicate that changing the direction of the amide bond leads to a significant decrease in the compounds'activity,highlighting the critical role of the amide bond direction in modulating activity.
作者
眭超阳
刘一朝
刘莹莹
戴书通
马明远
李心如
范奇盼
周思雨
钱宇卿
李铭东
SUI Chaoyang;LIU Yizhao;LIU Yingying;DAI Shutong;MA Mingyuan;LI Xinru;FAN Qipan;ZHOU Siyu;QIAN Yuqing;LI Mingdong(School of Pharmacy,Jiangxi University of Chinese Medicine,Nanchang 330006,China)
出处
《中国药物化学杂志》
2025年第6期428-435,共8页
Chinese Journal of Medicinal Chemistry
基金
江西中医药大学博士启动基金项目(2022BSZR005、2022BSZR006、2019BSZR002)。
