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Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors
- Source :
- Organic & Biomolecular Chemistry. 14:6304-6315
- Publication Year :
- 2016
- Publisher :
- Royal Society of Chemistry (RSC), 2016.
-
Abstract
- A series of quinolone-2-(1H)-ones derived from the Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line. A focused SAR study was conducted and revealed core characteristics of the quinolone-2-(1H)-ones required for cytotoxicity. These requirements included a C3-tethered indole moiety, an indole C5-methyl moiety, an aliphatic tail or an ester, as well as an additional aromatic moiety. Further investigation in the SAG-activated Shh-LIGHT2 cell line with the most active analogues: 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (5), 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (23) and ethyl (2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)acetyl)glycinate (24) demonstrated a down regulation of the HSP via a reduction in Gli expression, and in the mRNA levels of Ptch1 and Gli2. Analogues 5, 23 and 24 returned in cell inhibition values of 11.6, 2.9 and 3.1 μM, respectively, making this new HSP-inhibitor pharmacophore amongst the most potent non-Smo targeted inhibitors thus far reported.
- Subjects :
- 0301 basic medicine
Stereochemistry
Antineoplastic Agents
Quinolones
Biochemistry
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Downregulation and upregulation
Cell Line, Tumor
Humans
Moiety
Hedgehog Proteins
Physical and Theoretical Chemistry
Cytotoxicity
Cell Proliferation
Indole test
Dose-Response Relationship, Drug
Molecular Structure
Organic Chemistry
Hedgehog signaling pathway
030104 developmental biology
chemistry
Cell culture
Drug Screening Assays, Antitumor
Pharmacophore
Acetamide
Signal Transduction
Subjects
Details
- ISSN :
- 14770539 and 14770520
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Organic & Biomolecular Chemistry
- Accession number :
- edsair.doi.dedup.....1c06cc240793fb869da3facbd392f374