Journal
CHEMISTRY & BIODIVERSITY
Volume 16, Issue 12, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbdv.201900431
Keywords
aminothiazole; Gli1; hedgehog signaling; Smo; synthesis; cytotoxicity; benzimidazole
Funding
- Liaoning Science and Technology Project Management [20170520026]
- Science and Technology Fund Project of Shenyang Medical College [20174045, 20191027]
- Science and Technology Program of Shenyang [18-013-0-99]
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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.
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