异羟肟酸类化合物对突变型EGFR细胞的生物活性研究  

Activity evaluation for isohydroxamic acid.compounds on mutant EGFR cell lines

作　　者：何林洪 张洁 曾宪霞 凌珍 谭凯丽 周立正 王闻楚[2] HE Linhong;ZHANG Jie;ZENG Xianxia;LING Zhen;TAN Kaili;ZHOU Lizheng;WANG Wenchu(Pharmaceutical College,Guangxi Medical University,Nanning 530021,China;School of Basic Medical Sciences,Guangxi Medical University,Nanning 530021,China)

机构地区：[1]广西医科大学药学院,广西南宁530021 [2]广西医科大学基础医学院,广西南宁530021

出　　处：《沈阳药科大学学报》2024年第8期1018-1025,1073,共9页Journal of Shenyang Pharmaceutical University

基　　金：国家自然科学基金资助项目(82160448、81803350和82260673);广西自然科学基金面上基金资助项目(2022JJA140155)。

摘　　要：目的设计并合成具有抗突变型表皮生长因子(epidermal growth factor receptor,EGFR)驱动的非小细胞肺癌(non-small cell lung cancer,NSCLC)活性的结构新颖的先导化合物。方法一系列异羟肟酸类衍生物由起始原料4-氯-7H-吡咯并[2,3-d]嘧啶经7步化学反应合成而得,采用MTT法测定目标化合物在体外对野生型EGFR(H460和A549)和突变型EGFR(PC9、HCC827和H1975)细胞系的抗增殖活性。结果10个异羟肟酸类目标化合物结构由NMR和MS谱鉴定确证。活性研究表明,以直链烷基取代的异羟肟酸衍生物(A1、A2和A4-A6)能有效抑制突变型EGFR细胞系的增殖,而其他化合物如A3和B1-B4则无法有效抑制上述细胞的增殖。其中,化合物A4表现最优,不仅能高效抑制突变型EGFR细胞系PC9、HCC827和H1975细胞系的增殖,ID_(50)值小于7μmol·L^(-1),与阳性对照N′-羟基-N-苯基辛二酰胺(SAHA)生物活性相似,而且选择性较好,其抑制野生型EGFR细胞系H460和A549增殖的ID_(50)值大于32μmol·L^(-1)。结论化合物A4可作为突变型EGFR抑制剂的先导化合物进行深度开发。Objective To design and synthesize novel.compounds that possessed the anti-proliferative activities against non-small cell lung cancer(NSCLC) cell lines with mutant epidermal growth factor receptor(EGFR).Methods A series of isohydroxamic acid derivatives were synthesized from the raw material of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine through seven steps.The anti-proliferative activities against cell lines with wild EGFR and mutant EGFR for target.compounds were test by MTT assay.Results All.compounds were identified by NMR and MS.In vitro bioactivities study demonstrated that.compounds(A1-A2,A4-A6) with straight chain alkyl substituted isohydroxamic acid displayed anti-proliferative activities against EGFR mutant cell lines,whereas,the rest.compounds including A3 and B1-B4 gave the negative results.Among them,compound A4 exhibited the best anti-proliferative activity against PC9,HCC827 and H1975 with ID_(50) values smaller than 7 μmol·L~(-1),which was similar to that of the positive control N′-Hydroxy-N-phenyloctanediamide(SAHA).Moreover,compound A4 could not inhibit the proliferation of EGFR wild type cell lines H460(ID_(50)>32 μmol·L~(-1)) and A549(ID_(50)>32 μmol·L~(-1)),suggesting the good selectivity of A4 had a good selectivity.Conclusions.compound A4 can be regard as a lead.compound for the developing of mutant EGFR inhibitors.

关 键 词：异羟肟酸 非小细胞肺癌 表皮生长因子受体 突变型 选择性 

分 类 号：R914[医药卫生—药物化学]