Dichlorophenylacrylonitriles as AhR Ligands That Display Selective Breast Cancer Cytotoxicity in vitro

ChemMedChem
Jennifer R BakerA McCluskey

Abstract

Knoevenagel condensation of 3,4-dichloro- and 2,6-dichlorophenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (5) and (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile (6) displayed 0.56±0.03 and 0.127±0.04 μm growth inhibition (GI50 ) and 260-fold selectivity for the MCF-7 breast cancer cell line. A 2,6-dichlorophenyl moiety saw a 10-fold decrease in potency; additional nitrogen moieties (-NO2 ) enhanced activity (Z)-2-(2,6-dichloro-3-nitrophenyl)-3-(2-nitrophenyl)acrylonitrile (26) and (Z)-2-(2,6-dichloro-3-nitrophenyl)-3-(3-nitrophenyl)acrylonitrile (27), with the corresponding -NH2 analogues (Z)-2-(3-amino-2,6-dichlorophenyl)-3-(2-aminophenyl)acrylonitrile (29) and (Z)-2-(3-amino-2,6-dichlorophenyl)-3-(3-aminophenyl)acrylonitrile (30) being more potent. Despite this, both 29 (2.8±0.03 μm) and 30 (2.8±0.03 μm) were found to be 10-fold less cytotoxic than 6. A bromine moiety effected a 3-fold enhancement in solubility with (Z)-3-(5-bromo-1H-pyrrol-2-yl)-2-(3,4-dichlorophenyl)acrylonitrile 18 relative to 5 at 211 μg mL-1 . Modeling-guided synthesis saw the introduction of 4-aminophenyl substituents (Z)-3-(4-aminophenyl)-2-(3,4-dichloro...Continue Reading

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Citations

Jan 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mara Di FilippoMarcus Baumann
Nov 14, 2019·Medicinal Research Reviews·Jennifer R BakerAdam McCluskey
May 5, 2021·Journal of Computer-aided Molecular Design·David T StantonStefan Paula
May 28, 2021·Toxicology Letters·A PatatianM L Follet-Gueye
Jul 16, 2021·RSC Medicinal Chemistry·Jennifer R BakerJennette A Sakoff

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