摘要
目的以Ex-Rad为先导化合物,设计合成含有砜类结构的新型小分子蛋白酪氨酸激酶(PTK)抑制剂,并对其抑酶活性进行初步评价。方法以(对氯)氯苄为起始原料,通过亲核取代、氧化以及缩合反应合成目标化合物;采用酶联免疫法对目标化合物进行PTK抑制活性的测定。结果合成了3个含砜结构的目标化合物,结构经~1H-NMR确证。活性筛选结果表明,在浓度为100μmol·L^(-1)和1 mmol·L^(-1)时,目标化合物WT001的PTK抑制率分别为(3.5±1.7)%和(5.7±1.1)%,WT002抑制率分别为(50.6±2.7)%和(40.3±0.7)%,WT003抑制率分别为(33.7±3.1)%和(44.3±5.9)%,阳性药Ex-Rad的抑制率分别为(7.0±2.1)%和(35.4±4.1)%。结论在目标化合物中WT002和WT003显示出较强的PTK抑制活性,且活性高于同浓度的Ex-Rad。
Objective To synthesize novel small molecule protein tyrosine kinase（PTK） inhibitors containing sulfone structure using Ex-Rad as a lead compound,and to conduct a preliminary evaluation of their inhibitory activity.Methods The target compounds were synthesized in three steps：nucleophilic substitution,oxidation and condensation,using（p-chlorobenzoyl） benzyl chloride as a starting material.The PTK inhibitory activitiy of the target compounds was evaluated by enzyme-linked immunosorbent assay（ELISA）.Results Three target compounds with sulfone structure were synthesized,the structures of which were confirmed by ^1H- NMR.Activity screening results showed that at the concentration of 100 μmol ·^-1 and 1 mmol·L^-1,the target compound WT001 had a tyrosine kinase inhibition rate of（3.5 ± 1.7）%and（5.7 ±1.1）%respectively,WT002（50.6 ±2.7）%and（40.3＋0.7）%respectively,and WT003（33.7±3.1）%and（44.3±5.9）%respectively.The control drug ExRad had an inhibition rate of（7.0 ±2.1）%and（35.4 ±4.1）%respectively.Conclusion The target compounds WT002 and WT003 show stronger inhibitory activity of PTK than Ex-Rad at the same concentration.
出处
《解放军药学学报》
CAS
CSCD
2015年第3期190-193,共4页
Pharmaceutical Journal of Chinese People's Liberation Army
基金
国家自然科学基金资助项目
No.81273431
81072531
30770655
21102176
21272273
关键词
砜类化合物
蛋白酪氨酸激酶抑制剂
合成
sulfone compounds
protein tyrosine kinase inhibitor
synthesis
