Dichlorophenylacrylonitriles as AhR Ligands displaying selective breast cancer cytotoxicity in vitro

    Jennifer R Baker1, Jayne Gilbert2, Stefan Paula3, Xiao Zhu3, Jennette A Sakoff2, Adam McCluskey1

    • 1 The University of Newcastle, Chemistry, Newcastle, Australia
    • 2 Calvary Mater Hospital, Medical Oncology, Newcastle, Australia
    • 3 Purdue University, Chemistry, West Lafayette, United States

    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 10‐206 nM potency against MDAMB468, T47D, ZR‐75‐1, SKBR3 and BT474. MOE docking scores showed a good correlation between predicted binding efficiencies and observed MCF‐7 cytotoxicity. This supports the use of this model in developing breast cancer specific drugs.

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