Design, synthesis and evaluation of novel indole derivatives as AKT inhibitors

Bioorg Med Chem. 2014 Jan 1;22(1):366-73. doi: 10.1016/j.bmc.2013.11.022.

Dezhi Yang ¹, Peng Wang ¹, Jianzhen Liu ¹, Hualu Xing ¹, Yang Liu ¹, Wencheng Xie ¹, Guisen Zhao ²

Affiliations

1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China.
2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: guisenzhao@sdu.edu.cn.

PMID: 24308997 DOI: 10.1016/j.bmc.2013.11.022

Abstract

Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel Akt inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against Akt1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate Cancer cell line.

Keywords

AKT inhibitors; GSK3β; Inhibition rate; Tetra-substituted indoles.

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