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Synthesis and Evaluation of Aminothiazole Derivatives as Hedgehog Pathway Inhibitors
Author(s) -
Sun Chiyu,
Zhang Ying,
Lin Lin,
Liu Shuyuan,
Wang Rui,
Zang Wei,
Meng Weijia,
Chen Xiaofeng
Publication year - 2019
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201900431
Subject(s) - smoothened , chemistry , hedgehog , hedgehog signaling pathway , gli1 , cytotoxicity , benzimidazole , du145 , thiazole , microbiology and biotechnology , stereochemistry , biochemistry , signal transduction , cancer cell , in vitro , biology , cancer , genetics , organic chemistry , lncap
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‐(1 H ‐benzimidazol‐2‐yl)‐4‐chloroanilino]‐ N ‐[4‐(trifluoromethyl)phenyl]‐1,3‐thiazole‐4‐carboxamide), with IC 50 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.