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‐dichlorophenyl)acrylonitrile (35) and (Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide (38), with respective GI₅₀ values of 0.030±0.014 and 0.034±0.01 μm. Other analogues such as 35 and 36 were found to have sub‐micromolar potency against our panel of cancer cell lines (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 compound 38 against the U87 cell line. 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. Molecular Operating Environment docking scores showed a good correlation between predicted binding efficiencies and observed MCF‐7 cytotoxicity. This supports the use of this model in the development of breast‐cancer‐specific drugs.

中文翻译：

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二氯苯基丙烯腈作为在体外表现出选择性乳腺癌细胞毒性的AhR配体

3,4-二氯和2,6-二氯苯基乙腈的Knoevenagel缩合得到二氯苯基丙烯腈的文库。我们的铅（Z）-2-（3,4-二氯苯基）-3-（1 H-吡咯-2-基）丙烯腈（5）和（Z）-2-（3,4-二氯苯基）-3-（ 4-硝基苯基）丙烯腈（6）显示0.56±0.03和0.127±0.04μ米生长抑制（GI ₅₀）和260倍的选择性为MCF-7乳腺癌细胞系。2,6-二氯苯基部分的效价降低了10倍；额外的氮部分（-NO ₂）增强了活性（Z）-2-（2,6-二氯-3-硝基苯基）-3-（2-硝基苯基）丙烯腈（26）和（Z）-2-（2,6-二氯-3-硝基苯基）-3-（3-硝基苯基）丙烯腈（27），以及相应的NH ₂类似物（Z）-2-（3-氨基-2,6 -二氯苯基）-3-（2-氨基苯基）丙烯腈（29）和（Z）-2-（3-氨基-2-6,6-二氯苯基）-3-（3-氨基苯基）丙烯腈（30）更有效。尽管如此，这两个29（2.8±0.03μ米）和30（2.8±0.03μ米）被认为是10倍小于细胞毒性6。溴部分使（Z）-3-（5-溴-1 H的溶解度提高了3倍吡咯-2-基）-2-（3,4-二氯苯基）丙烯腈18相对于5在211μgmL ^-1下。在模型指导下的合成过程中，引入了4-氨基苯基取代基（Z）-3-（4-氨基苯基）-2-（3,4-二氯苯基）丙烯腈（35）和（Z）-N-（4-（2-氰基-2-（3,4-二氯苯基）乙烯基）苯基）乙酰胺（38），与相应的GI _50倍0.030±0.014的值和0.034±0.01μ米。其他类似物，例如35和36被发现对我们的癌细胞系（HT29，结肠; U87和SJ-G2，胶质母细胞瘤; A2780，卵巢; H460，肺; A431，皮肤; Du145，前列腺; BE2-C，神经母细胞瘤; MIA（胰腺； SMA，鼠胶质母细胞瘤），但针对U87细胞系的化合物38除外。在一组耐药乳腺癌细胞系中对38（（Z）-N-（4-（2-氰基-2-（3,4-二氯苯基）乙烯基）苯基）乙酰胺的更广泛评估显示10- 206牛顿米对MDAMB468，T47D，ZR‐75‐1，SKBR3和BT474的效力。分子操作环境对接分数显示预测的结合效率与观察到的MCF-7细胞毒性之间具有良好的相关性。这支持在乳腺癌特异性药物的开发中使用该模型。