N'-苯亚甲基-2-(3-吡啶基)喹啉-4-酰肼衍生物的合成及抗肿瘤活性

Synthesis and anti-tumor activity of N'-phenylmethylene-2-(3-pyridyl)quinoline-4-acylhydrazine derivatives

以N-[5-(呋喃-2-基)-1,3,4-二唑-2-基]-2-苯基-喹啉-4-甲酰胺(STX-0119)为先导化合物,基于生物电子等排原理设计、合成了25个N’-苯亚甲基-2-(3-吡啶基)喹啉-4-酰肼衍生物(收率20.4%~42.6%)。通过1HNMR、13CNMR、HRMS确证了产物结构,采用噻唑蓝(MTT)和台盼蓝法以人乳腺癌细胞(MCF-7细胞)、人非小细胞肺癌细胞(A549细胞)、人慢性髓原白血病细胞(K562细胞)、人急性淋巴白血病细胞(RS4:11细胞)为测试细胞株评价了目标化合物的体外抗肿瘤活性。目标化合物N’-(2-羟基-5-硝基苄叉)-2-(3-吡啶基)喹啉-4-酰肼(Ⅶr)表现出最强的抗A549细胞增殖活性[半抑制浓度(IC_(50))=(7.4±0.8)μmol/L];N’-(2-羟基-5-溴苄叉)-2-(3-吡啶基)喹啉-4-酰肼(Ⅶq)表现出最强的抗RS4:11细胞增殖活性[IC_(50)=(2.4±0.2)μmol/L];N’-(4-溴苄叉)-2-(3-吡啶基)喹啉-4-酰肼(Ⅶl)不仅表现出最强的抗MCF-7细胞增殖活性[IC_(50)=(4.9±0.3)μmol/L],还表现出最强抗K562细胞增殖活性[IC_(50)=(1.2±0.2)μmol/L]。分子对接结果显示,产物Ⅶl发挥抗肿瘤的作用可能与STAT3通路有关,值得进一步深入研究。

Twenty-five N'-phenylmethylene-2-(3-pyridyl)quinoline-4-hydrazide derivatives(yield in 20.4%~42.6%)were designed and synthesized based on bioelectronic isosteric principle with N-[5-(furan-2-yl)-1,3,4-oxadiazol-2-yl]-2-phenylquinoline-4-carboxamide(STX-0119)as lead compound,and confirmed by 1HNMR,13CNMR and MS.The in vitro antitumor activity of the target compounds was evaluated by thiazolyl blue(MTT)assay and trypan blue assay using human breast cancer cell line(MCF-7 cells),human lung cancer cell line(A549 cells),human chronic myelogenous leukemia cell line(K562 cells),and human acute B-lymphoblastic leukemia cell line(RS4:11 cells)as test cell lines.Target compound N'-(2-hydroxy-5-nitrobenzyl)-2-(3-pyridyl)quinoline-4-hydrazide(Ⅶr)exhibited the strongest cell proliferation inhibitory activity against A549 cells with a half-inhibitory concentration(IC_(50))of(7.4±0.8)μmol/L;Target compound N'-(2-hydroxy-5-bromobenzyl)-2-(3-pyridyl)quinoline-4-hydrazide(Ⅶq)showed the strongest activity against RS4:11 cell proliferation with IC_(50) of(2.4±0.2)μmol/L;And target compound N'-(4-bromobenzyl)-2-(3-pyridyl)quinoline-4-hydrazide(Ⅶl)displayed the strongest activity against MCF-7 cells[IC_(50)=(4.9±0.3)μmol/L]and K562 cells[IC_(50)=(1.2±0.2)μmol/L].Molecular docking result indicated that the anti-tumor activity of compoundⅦl might be related to the STAT3 pathway,which was worthy of further in-depth research.