含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究
收稿日期: 2023-05-18
修回日期: 2023-08-16
网络出版日期: 2023-09-15
基金资助
浙江省自然科学基金(LGF20B020001); 浙江省自然科学基金(LGF21H160034); 国家自然科学基金(81903074)
Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides
Received date: 2023-05-18
Revised date: 2023-08-16
Online published: 2023-09-15
Supported by
Natural Science Foundation of Zhejiang Province(LGF20B020001); Natural Science Foundation of Zhejiang Province(LGF21H160034); National Natural Science Foundation of China(81903074)
为了寻找高效抗肿瘤活性化合物, 根据药物化学拼合原理, 在姜黄素骨架中引入酰胺键和3,4-二氯取代, 设计并合成了19个新型含有3,4-二氯苯基的酰胺类化合物. 用噻唑蓝比色法(MTT)检测化合物对AGS和BGC-823胃癌细胞的体外抗肿瘤活性. 结果表明, 部分化合物表现出良好的抑制胃癌细胞生长的活性, 其中(2E)-3-(3,4-二氯苯基)- 1-(2-{3-[4-(三氟甲基)苯基]丙酰基}乙氮基)丙-2-烯-1-酮(17)对AGS细胞的半数抑制浓度(IC50)值为(1.94±0.94) μmol/L. 此外, 细胞集落形成、划痕、流式细胞术以及蛋白质印迹(Western blot)实验结果表明, 化合物17能明显抑制AGS细胞的生长和迁移, 阻滞细胞周期于G0/G1期, 并诱导促凋亡相关蛋白多聚腺苷二磷酸核糖聚合酶降解产物(Cleaved- PARP)及Bcl-2相关X蛋白(Bax)呈剂量依赖性上调, 诱导抗凋亡蛋白Bcl-2下调, 从而诱导细胞凋亡. 初步的机制研究显示, 化合物17可能通过抑制双特异性酪氨酸磷酸化调节激酶1A (DYRK1A)-蛋白激酶B (PKB, AKT)信号通路起到体外抗胃癌作用. 综上所述, 研究结果表明含有3,4-二氯苯基的酰胺类化合物可能是一类有药用研究前景的小分子化合物, 化合物17有望成为一种抗肿瘤候选化合物.
王博珍 , 张婕 , 粘春惠 , 金茗茗 , 孔苗苗 , 李物兰 , 何文斐 , 吴建章 . 含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究[J]. 有机化学, 2024 , 44(1) : 232 -241 . DOI: 10.6023/cjoc202305025
In order to find efficient antitumor compounds, 19 novel 3,4-dichlorophenyl amides were designed and synthesized by introducing amide bonds and 3,4-dichloro substitution into the curcumin skeleton according to the principles of medicinal chemistry combination. The in vitro antitumor activity of the compounds against AGS and BGC-823 gastric cancer cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results showed that some compounds displayed potential inhibitory activity. Notably, (2E)-3-(3,4-dichlorophenyl)-1-(2-(3-(4-(trifluoromethyl)phenyl)propio- nyl)ethylazo)propan-2-en-1-one (17) showed potent growth inhibition on AGS with a half maximal inhibitory concentration (IC50) value of (1.94±0.94) μmol/L. Besides, the results of cell colony formation, wound healing, flow cytometry and western blot showed that compound 17 significantly inhibited the growth and migration of AGS cells, arrested the cell cycle in G0/G1 phase, and induced a dose-dependent up-regulation of the pro-apoptotic proteins such as cleaved poly ADP-ribose polymerase (Cleaved-PARP) and Bcl2-associated X protein (Bax), and a down-regulation of the anti-apoptotic protein Bcl-2, thus inducing cell apoptosis. Preliminary mechanistic studies suggested that compound 17 may exert its anti-gastric cancer effects in vitro by inhibiting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A)-protein kinase B (PKB, AKT) signaling pathway. In conclusion, this study indicates that amide compounds containing 3,4-dichlorophenyl may be a class of small molecule compounds with promising prospects for medicinal research, and compound 17 is expected to be an antitumor candi-date.
Key words： curcumin analog; 3,4-dichlorophenyl; amide bond; synthesis; antitumor activity
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