摘要
通过合成得到了一系列新颖的苯并[b]氧杂棘-5(2H)-酮类化合物单晶,结构经~1HNMR,^(13)CNMR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]氧杂棘-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]氧杂棘-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]氧杂棘-5(2H)-酮(8i)对ErbB1和ErbB2的IC50分别为1.0和0.33μmol/L,8n对RET的IC_(50)为0.7μmol/L,7-[(3,4-二羟基苯基)甲基]氨基-2,3,4,5-四氢-苯并[b]氧杂棘-5-醇(10b)对ErbB2的IC_(50)为1.02μmol/L.
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. Erb B1, Erb B2, 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 IC_(50) value for 8n against RET is 0.7 μmol/L, while the IC_(50) value for7-[(3,4-dihydroxyphenyl)methyl]amino-2,3,4,5-tetrahydro-benzo[b]oxazepin-5-ol(10b) against ErbB2 is 1.02 μmol/L.
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
2017年第6期1463-1472,共10页
Chinese Journal of Organic Chemistry
基金
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~~