Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant

Daoguang Zhang; Dongdong Tong; Dezhi Yang; Jing Sun; Fenghe Zhang; Guisen Zhao

doi:10.1039/C8MD00197A

Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant

Daoguang Zhang,†^a Dongdong Tong,†^b Dezhi Yang,

^c Jing Sun,^d Fenghe Zhang*^b and Guisen Zhao

*^a

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* Corresponding authors

^a Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China
E-mail: guisenzhao@sdu.edu.cn
Fax: +86 531 88382009
Tel: +86 531 88382009

^b Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, Shandong 250012, PR China
E-mail: zfengh@sdu.edu.cn
Fax: +86 531 88382961
Tel: +86 531 88382961

^c National Pharmaceutical Experimental Teaching Demonstration Center, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563003, PR China

^d Department of Bone Metabolism, School of Stomatology, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, Shandong 250012, PR China

Abstract

A series of AKT inhibitors possessing a piperidin-4-yl side chain was designed and synthesized. Some of them showed high AKT1 inhibitory activity and potent anti-proliferative effect on PC-3 prostate cancer cells in the preliminary screening. Further studies revealed the most potent compound, 10h, as a pan-AKT inhibitor. Compound 10h was able to inhibit the cellular phosphorylation of AKT effectively and induce apoptosis of PC-3 cells. It also showed high metabolic stability in human liver microsomes. Preclinical characterization of 10h, a promising lead AKT inhibitor, as a potential anti-prostate cancer therapeutic needs to be further investigated.

Article information

https://doi.org/10.1039/C8MD00197A

Article type

Research Article

Submitted

13 Apr 2018

Accepted

28 Jun 2018

First published

03 Jul 2018

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Med. Chem. Commun., 2018,9, 1340-1350

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Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant

D. Zhang, D. Tong, D. Yang, J. Sun, F. Zhang and G. Zhao, Med. Chem. Commun., 2018, 9, 1340 DOI: 10.1039/C8MD00197A

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Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant

Abstract

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Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant

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