Dichlorophenylacrylonitriles as AhR Ligands displaying selective breast cancer cytotoxicity in vitro.

Dichlorophenylacrylonitriles as AhR Ligands displaying selective breast cancer cytotoxicity in vitro. ChemMedChem. 2018 May 17;: Authors: Baker JR, Gilbert J, Paula S, Zhu X, Sakoff JA, McCluskey A Abstract Knoevenagel condensation of 3,4-dichloro- and 2,6-dichloro- phenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads 5 and 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 potency loss; additional nitrogen moieties (-NO₂) enhanced activity (26 and 27), with the corresponding -NH₂ analogues (29 and 30) more potent. Despite this, both 29 (2.8±0.03 μM) and 30 (2.8±0.03 μM) were 10-fold less cytotoxic than 6. A bromine moiety effected a 3-fold enhancement in solubility with 18 relative to 5 at 211 μg mL-1. Modelling led synthesis saw the introduction of 4-aminophenyl substituent gave 35 and 38, 0.030±0.014 and 0.034±0.01 μM potent, respectively. Other analogues, e.g. 35 and 36, were sub-micromolar potent against our cell line panel (HT29, colon; U87 and SJ-G2, glioblastoma; A2780, ovarian; H460, lung; A431, skin; Du145, prostate; BE2-C neuroblastoma; MIA, pancreas and SMA murine glioblastoma) except 35 against U87. A more extensive evaluation of 38 ((Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide), in a panel of drug resistant breast carcinoma cell lines showed...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research