- Title
- Amino alcohol acrylonitriles as activators of the aryl hydrocarbon receptor pathway: an unexpected MTT phenotypic screening outcome
- Creator
- Baker, Jennifer R.; Russell, Cecilia C.; Gilbert, Jayne; Sakoff, Jennette A.; McCluskey, Adam
- Relation
- ChemMedChem Vol. 15, Issue 6, p. 490-505
- Publisher Link
- http://dx.doi.org/10.1002/cmdc.201900643
- Publisher
- Wiley
- Resource Type
- journal article
- Date
- 2020
- Description
- Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI50=30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13 a-g) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho (17 a), meta (17 b) and para (13 f). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.
- Subject
- breast cancer cell; metabolic inactivation; amino alcohol; screening; Sustainable Development Goals; SDG 3; SDG 7
- Identifier
- http://hdl.handle.net/1959.13/1426714
- Identifier
- uon:38461
- Identifier
- ISSN:1860-7179
- Language
- eng
- Reviewed
- Hits: 916
- Visitors: 903
- Downloads: 1
Collections
Goal 7: Ensure access to affordable, reliable, sustainable and modern energy
Goal 3: Good Health and Well-Being
| Thumbnail | File | Description | Size | Format |
|---|