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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.

Author information

1
The University of Newcastle, Chemistry, University Drive, Callaghan, 2308, Newcastle, AUSTRALIA.
2
Calvary Mater Hospital, Medical Oncology, Eidith Street, Waratah, 2298, Newcastle, AUSTRALIA.
3
Calvary Mater Hospital, Medical Oncology, Eidith Street, Waratah, 2308, Newcastle, AUSTRALIA.
4
The University of Newcastle, Department of Chemistry, University Drive, Callaghan, 2308, Newcastle, AUSTRALIA.

Abstract

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.

KEYWORDS:

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

PMID:
32012442
DOI:
10.1002/cmdc.201900643

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