Zhang Jiankang, Lv Xiaoqing, Ma Xiaodong, Hu Yongzhou
Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, China.
College of Medicine, Jiaxing University, Jiaxing 314001, China.
Eur J Med Chem. 2017 Feb 15;127:509-520. doi: 10.1016/j.ejmech.2017.01.016. Epub 2017 Jan 11.
Recently, the phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been considered as promising targets for the treatment of cancer. Herein, we synthesized a series of N-(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as novel PI3K/mTOR dual inhibitors for cancer therapy. In the biological evaluation, compound 17e was identified as a potent PI3K/mTOR dual inhibitor, which significantly inhibit Class I PI3Ks, mTOR and phosphorylation of pAkt(Ser473) at low nanomolar level. Moreover, 17e display high potency against PC-3 cells (IC = 80 nM) in the anti-proliferative assay, and showed acceptable pharmacokinetic properties in vivo.
最近，磷酸肌醇3-激酶（PI3K）和雷帕霉素哺乳动物靶点（mTOR）被认为是治疗癌症的有前景的靶点。在此，我们合成了一系列N-(5-(喹啉-6-基)吡啶-3-基)苯磺酰胺作为用于癌症治疗的新型PI3K/mTOR双重抑制剂。在生物学评价中，化合物17e被鉴定为一种有效的PI3K/mTOR双重抑制剂，它在低纳摩尔水平下能显著抑制I类PI3K、mTOR和pAkt(Ser473)的磷酸化。此外，17e在抗增殖试验中对PC-3细胞显示出高效力（IC = 80 nM），并且在体内表现出可接受的药代动力学性质。
