新型2,4-二胺基喹唑啉类PAK4抑制剂的合成及其生物活性研究

Synthesis and activity evaluation of novel 2,4-diaminoquinazoline derivatives as PAK4 inhibitors

目的设计合成新型2,4-二胺基喹唑啉类PAK4小分子抑制剂,并对其抑酶活性进行评价。方法以5-氯-2-氨基苯甲酸为起始原料,经环合反应、氯代反应、两次芳香亲核取代反应,制备5-氯-2,4-二胺基喹唑啉类目标化合物;以3,4-二甲氧基苯甲酸为起始原料,经硝化反应、还原反应、环合反应、两次芳香亲核取代反应,制备6,7-二甲氧基-2,4-二胺基喹唑啉类目标化合物。采用Kinase-Glo激酶发光法测试目标化合物对PAK4的体外抑酶活性。结果与结论合成了11个未见文献报道的新型2,4-二胺基喹唑啉类化合物,目标物的结构经MS和1H-NM R谱确证;体外抑酶活性评价结果表明,目标化合物对PAK4具有较好的抑制活性,IC50值均小于30μmol·L-1,其中,活性较好的两个化合物(5b、5d)IC50值分别是8.66、11.71μmol·L-1,具有进一步研究的价值。

p21-activated kinase 4（ PAK4）,a serine / threonine protein kinase,has involved in the regulation of cytoskeletal reorganization,cell proliferation,gene transcription,oncogenic transformation and cell invasion.Moreover,PAK4 overexpression,genetic amplification and mutations were detected in a variety of human tumors,which make it potential therapeutic target. In our laboratory,the PAK4 inhibitor LCH-7749944 was obtained by the virtual screening technology of the computer. Structural modification of the LCH-7749944 was carried out to obtain our compounds. Two categories of derivatives of 2,4-diaminoquinazolins were designed,synthesized and evaluated for their PAK4 inhibitory activities. Starting from 2-amino-5-chlorobenzoic acid,followed by condensation,chlorination and two steps of nucleophilic substitution six newcompounds were synthesized. Starting from 3,4-dimethoxybenzoic acid,followed by nitration,reduction,condensation,chlorination and two steps of nucleophilic substitution five newcompounds were synthesized. Totally 11 target compounds were not reported by literature and have been confirmed by1H-NMR and MS analysis.Kinase-GloLuminescent Kinase Assay demonstrated that the inhibitory activities of nine compounds were better than the lead compound. Among of them,compounds 5b and 5d showed certain activities with IC50 values of 8. 66 μmol·L- 1and 11. 71 μmol·L- 1. As potential novel PAK4 inhibitors,derivatives of 2,4-diaminoquinazoline should be further investigated.