新颖3，4-二氢-苯并[b]氧杂(艹卓)-5（2H）-酮类化合物的合成以及蛋白酪氨酸激酶抑制活性研究
收稿日期: 2016-11-02
修回日期: 2017-01-09
网络出版日期: 2017-02-15
基金资助
国家自然科学基金（Nos.81520108028，81273430，21402010，21672230，41506187，81302692，41476063，4167060562，8160131016）、国家自然科学基金委员会-山东省人民政府联合资助海洋科学研究中心项目（No.U1406402）、上海市科委基金（Nos.14431901100，15431901000）、新药研究国家重点实验室项目（No.SIMM1501ZZ-03）、中国科学院药物创新研究院自主部署科研（No.CASIMM0120152039）资助项目.
Synthesis and Activity Evaluation of Novel 3,4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors
Received date: 2016-11-02
Revised date: 2017-01-09
Online published: 2017-02-15
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 81520108028, 81273430, 21402010, 21672230, 41506187, 81302692, 41476063, 4167060562, 8160131016), and the National Natural Science Foundation of China-Shandong Joint Fund for Marine Science Research Centers (No. U1406402), the Shanghai Science and Technology Committee Project (Nos. 14431901100, 15431901000), the State Key Laboratory of Drug Research/Shanghai Institute of Materia Medica Projects (No. SIMM1501ZZ-03), the Institutes for Drug Discovery and Development, Chinese Academy of Sciences (No. CASIMM0120152039).
通过合成得到了一系列新颖的苯并[b]氧杂(艹卓)-5（2H）-酮类化合物单晶，结构经1H NMR，13C NMR和HREIMS确证，E-7-[（2，5-二羟基苯基）甲亚基]氨基-3，4-二氢-苯并[b]氧杂(艹卓)-5（2H）-酮（8k）和E-7-[（2，3，4-三羟基苯基）亚基]氨基-3，4-二氢-苯并[b]氧杂(艹卓)-5-（2H）-酮（8n）的结构经单晶X衍射方法进一步确证.系统测试了化合物对蛋白酪氨酸激酶（PTKs），如ErbB1，ErbB2，c-Met，ALK，FGFR1，RET和KDR等的抑制活性，结果表明含有邻苯二酚片段的化合物对蛋白酪氨酸激酶具有显著的抑制活性，其中E-7-[（3，4-二羟基苯基）甲亚基]氨基-3，4-二氢-苯并[b]氧杂(艹卓)-5（2H）-酮（8i）对ErbB1和ErbB2的IC50分别为1.0和0.33 μmol/L，8n对RET的IC50为0.7 μmol/L，7-[（3，4-二羟基苯基）甲基]氨基-2，3，4，5-四氢-苯并[b]氧杂(艹卓)-5-醇（10b）对ErbB2的IC50为1.02 μmol/L.
关键词： 3; 4-二氢-苯并[b]氧杂(艹卓)-5（2H）-酮; 合成; 蛋白酪氨酸激酶抑制剂; ErbB1; ErbB2
侯桂革 , 江成世 , 刘红椿 , 童林江 , 彭霞 , 季寅淳 , 耿美玉 , 肖伟 , 龚景旭 , 郭跃伟 . 新颖3，4-二氢-苯并[b]氧杂(艹卓)-5（2H）-酮类化合物的合成以及蛋白酪氨酸激酶抑制活性研究[J]. 有机化学, 2017 , 37(6) : 1463 -1472 . DOI: 10.6023/cjoc201611005
A series of novel 3,4-dihydro-benzo[b]oxazepin-5(2H)-one derivatives were designed and synthesized as potent protein-tyrosine kinases (PTKs, e.g. ErbB1, ErbB2, c-Met, ALK, FGFR1, RET, KDR) inhibitors. All compounds were characterized by NMR and MS. E-7-[(2,5-dihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one (8k) and E-7-[(2,3,4-trihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one (8n) were further characterized by X-ray single-crystal analysis. The synthesized compounds were further tested for their inhibitory activity on PTKs. The results display compounds with catechol-substitution display the most potent inhibitory activities toward PTKs. The IC50 values for E-7-[(3,4-dihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one (8i) against ErbB1, ErbB2 are 1.0 and 0.33 μmol/L, respectively. The IC50 value for 8n against RET is 0.7 μmol/L, while the IC50 value for 7-[(3,4-dihydroxyphenyl)methyl]amino-2,3,4,5-tetrahydro-benzo[b]oxazepin-5-ol (10b) against ErbB2 is 1.02 μmol/L.
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