Synthesis and Evaluation of Aminothiazole Derivatives as Hedgehog Pathway Inhibitors

被引：2

作者：

Sun, Chiyu ^{[1
]}

Zhang, Ying ^{[2
]}

Lin, Lin ^{[1
]}

Liu, Shuyuan ^{[1
]}

Wang, Rui ^{[1
]}

Zang, Wei ^{[1
]}

Meng, Weijia ^{[1
]}

Chen, Xiaofeng ^{[3
]}

机构：

[1] Shenyang Med Coll, Coll Basic Med Sci, Shenyang 110034, Liaoning, Peoples R China

[2] Shenyang Univ Chem Technol, Sch Chem Engn, Shenyang 110142, Liaoning, Peoples R China

[3] Natl Res Inst Family Planning, Beijing 100081, Peoples R China

来源：

CHEMISTRY & BIODIVERSITY | 2019年 / 16卷 / 12期

关键词：

aminothiazole; Gli1; hedgehog signaling; Smo; synthesis; cytotoxicity; benzimidazole; SIGNALING PATHWAY; DRUG-RESISTANCE; ACYLTHIOUREA; GROWTH; POTENT; DISCOVERY; DESIGN;

D O I：

10.1002/cbdv.201900431

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 series of aminothiazole derivatives bearing the benzimidazole moiety were synthesized and evaluated in Gli luciferase reporter assays. Lead optimization led to the discovery of potent hedgehog pathway antagonist 18 (2-[3-(1H-benzimidazol-2-yl)-4-chloroanilino]-N-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carboxamide), with IC50 values in nanomolar range. The molecular basis ascribed to hindering sonic hedgehog-driven Smoothened (Smo) localization within the primary cilium (PC). Moreover, compound 18 inhibited Gli1 mRNA expression in mutant Smo cell line and displayed moderate cytotoxicity against DAOY cancer cell.

引用

页数：7

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