Shao Teng, Wang Juan, Chen Jian-Gang, Wang Xiao-Meng, Li Huan, Li Yi-Ping, Li Yan, Yang Guang-De, Mei Qi-Bing, Zhang San-Qi
Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China.
Eur J Med Chem. 2014 Mar 21;75:96-105. doi: 10.1016/j.ejmech.2014.01.053. Epub 2014 Jan 29.
2-Substituted-3-sulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides have been proposed as novel structures of PI3K inhibitors and anticancer agents based on bioisostere. In the present study, 2-substituted-3-sulfonamino-5-(4-morpholinoquinazolin-6-yl)benzamides and 2-methoxy-3-sulfonamino-5-(4-morpholinoquinolin-6-yl)benzamides were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines, including A549, HCT-116, U-87 MG and KB. The SAR of the title compounds was preliminarily discussed. Compound 1a with potent antiproliferative activity was tested for its inhibitory activity against PI3K and mTOR and its effect on the AKT and p-AKT(473). The anticancer effect of 1a was evaluated in established nude mice U-87 MG xenograft model. The results suggest that compound 1a can significantly inhibit PI3K/AKT/mTOR pathway and tumor growth. These findings strongly support the assumption that title compounds are potent PI3K inhibitors and anticancer agents.
基于生物电子等排体，2-取代-3-磺酰胺基-5-（喹唑啉-6-基或喹啉-6-基）苯甲酰胺已被提出作为PI3K抑制剂和抗癌剂的新型结构。在本研究中，合成了2-取代-3-磺酰胺基-5-（4-吗啉基喹唑啉-6-基）苯甲酰胺和2-甲氧基-3-磺酰胺基-5-（4-吗啉基喹啉-6-基）苯甲酰胺。通过MTT法评估了它们对包括A549、HCT-116、U-87 MG和KB在内的四种人类癌细胞系的体外抗增殖活性。初步讨论了标题化合物的构效关系。对具有强效抗增殖活性的化合物1a进行了PI3K和mTOR抑制活性以及对AKT和p-AKT(473)影响的测试。在已建立的裸鼠U-87 MG异种移植模型中评估了1a的抗癌效果。结果表明化合物1a可显著抑制PI3K/AKT/mTOR通路和肿瘤生长。这些发现有力地支持了标题化合物是强效PI3K抑制剂和抗癌剂的假设。
