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ChemMedChem. 2020 Feb 3. doi: 10.1002/cmdc.201900643. [Epub ahead of print]

Amino Alcohol Acrylonitriles as Activators of the Aryl hydrocarbon Receptor Pathway, An Unexpected MTT Phenotypic Screening Outcome.

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The University of Newcastle, Chemistry, University Drive, Callaghan, 2308, Newcastle, AUSTRALIA.
Calvary Mater Hospital, Medical Oncology, Eidith Street, Waratah, 2298, Newcastle, AUSTRALIA.
Calvary Mater Hospital, Medical Oncology, Eidith Street, Waratah, 2308, Newcastle, AUSTRALIA.
The University of Newcastle, Department of Chemistry, University Drive, Callaghan, 2308, Newcastle, AUSTRALIA.


Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI50 = 30nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13a-g) to introduce additional hydrophobic moieties 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 via the ortho (17a), meta (17b) and para (13f). 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 23b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.


Breast cancer; MTT assay; SRB assay; aryl hydrocarbon receptor; dichlorophenylacrylonitriles


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