Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold

被引：4

作者：

Yang, Dezhi ^{[1
]}

Tong, Dongdong ^{[2
]}

Zhang, Qian ^{[1
]}

Wang, Yongtao ^{[1
]}

Sun, Jing ^{[3
]}

Zhang, Fenghe ^{[2
]}

Zhao, Guisen ^{[1
]}

机构：

[1] Shandong Univ, Dept Med Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci, Jinan, Shandong, Peoples R China

[2] Shandong Univ, Dept Oral & Maxillofacial Surg, Shandong Prov Key Lab Oral Tissue Regenerat, Sch Stomatol, Jinan, Shandong, Peoples R China

[3] Shandong Univ, Shandong Prov Key Lab Oral Tissue Regenerat, Sch Stomatol, Dept Bone Metab, Jinan, Shandong, Peoples R China

来源：

CHEMICAL BIOLOGY & DRUG DESIGN | 2017年 / 90卷 / 05期

基金：

中国国家自然科学基金;

关键词：

Akt1; inhibitors; antiproliferative activity; GSK3; indole scaffold; MITSUNOBU REACTIONS; BREAST-CANCER; DISCOVERY; THERAPY; KINASE; POTENT; TUMORS;

D O I：

10.1111/cbdd.13000

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 10nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3 protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50 value of 3.1 +/- 0.1m than positive control (15.5 +/- 0.4m). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.

引用

页码：791 / 803

页数：13

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