Yang Dezhi, Tong Dongdong, Zhang Qian, Wang Yongtao, Sun Jing, Zhang Fenghe, Zhao Guisen
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
Department of Oral and Maxillofacial Surgery, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
Chem Biol Drug Des. 2017 Nov;90(5):791-803. doi: 10.1111/cbdd.13000. Epub 2017 May 7.
A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10 nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC value of 3.1 ± 0.1 μm than positive control (15.5 ± 0.4 μm). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
设计并合成了一系列新型的具有吲哚骨架的潜在Akt1抑制剂。评估了它们对PC-3细胞系的抗增殖活性以及对Akt1的酶抑制活性。其中，一些化合物与GSK690693阳性对照相比，表现出更强的抗增殖活性和更强的Akt1抑制活性。特别是，化合物19b对Akt1表现出最有效的抑制活性，在浓度为10纳米时抑制率为70.3%。此外，化合物19b可以剂量依赖性地降低PC-3细胞系中下游GSK3β蛋白的磷酸化，并且对PC-3细胞系的抗增殖活性比阳性对照（15.5±0.4微米）高五倍，IC值为3.1±0.1微米。在此，化合物19b可能作为基于吲哚骨架的新型Akt1抑制剂进一步优化和开发的有前景的先导化合物。
