Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors

被引：24

作者：

Liu, Tingting ^{[1
]}

Wan, Yichao ^{[2
]}

Liu, Renshuai ^{[1
]}

Ma, Lin ^{[1
]}

Li, Minyong ^{[1
]}

Fang, Hao ^{[1
]}

机构：

[1] Shandong Univ, Minst Educ, Sch Pharm, Dept Med Chem,Key Lab Chem Biol, Jinan 250012, Shandong, Peoples R China

[2] Hunan Univ Sci & Technol, Minist Educ, Coll Chem & Chem Engn, Key Lab Theoret Organ Chem & Funct Mol, Xiangtan 411201, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 06期

基金：

中国国家自然科学基金;

关键词：

Bcl-2/Mcl-1; Indole-3-carboxylic acid-based derivatives; Anti-tumor; Inhibitors; SMALL-MOLECULE INHIBITORS; BCL-2; INHIBITORS; CANCER-THERAPY; CELL; PROTEINS; DERIVATIVES; DISCOVERY; APOPTOSIS; RESISTANCE; COMPOUND;

D O I：

10.1016/j.bmc.2017.02.014

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：

The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-X-L protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a K, value of 0.26 mu M for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a K-i value of 72 nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not BcI-X-L protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：1939 / 1948

页数：10

共 24 条

[1] Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-XL [J].