Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.
Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Hospital, Edith Street, Waratah, NSW, 2298, Australia.
ChemMedChem. 2018 Jul 18;13(14):1447-1458. doi: 10.1002/cmdc.201800256. Epub 2018 Jul 2.
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 (GI ) 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 (-NO ) 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 -NH 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 . 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 GI 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.
3,4-二氯苯乙腈和 2,6-二氯苯乙腈的 Knoevenagel 缩合得到了一系列二氯苯丙烯腈。我们的先导化合物（Z）-2-(3,4-二氯苯基）-3-(1H-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）对 MCF-7 乳腺癌细胞系的生长抑制（GI）分别为 0.56±0.03 和 0.127±0.04 μm，选择性为 260 倍。2,6-二氯苯基部分的效力降低了 10 倍；额外的氮部分（-NO）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），相应的 -NH 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-2,6-二氯苯基）-3-(3-氨基苯基)丙烯腈（30）更有效。尽管如此，29（2.8±0.03 μm）和 30（2.8±0.03 μm）的细胞毒性均比 6 低 10 倍。溴原子使（Z）-3-(5-溴-1H-吡咯-2-基)-2-(3,4-二氯苯基)丙烯腈 18 的溶解度提高了 3 倍，而与 5 相比，在 211μg/mL 时，其溶解度提高了 3 倍。基于模型的合成引入了 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），其 GI 值分别为 0.030±0.014 和 0.034±0.01 μm。其他类似物，如 35 和 36，对我们的癌细胞系（HT29，结肠；U87 和 SJ-G2，神经胶质瘤；A2780，卵巢；H460，肺；A431，皮肤；Du145，前列腺；BE2-C，神经母细胞瘤；MIA，胰腺；和 SMA，鼠神经胶质瘤）的效力低于亚微米，除了化合物 38 对 U87 细胞系的效力。对 38（（Z）-N-(4-(2-氰基-2-(3,4-二氯苯基)乙烯基)苯基)乙酰胺）在一组耐药乳腺癌细胞系中的更广泛评估显示，对 MDAMB468、T47D、ZR-75-1、SKBR3 和 BT474 的效力为 10-206 nm。分子操作环境对接评分显示预测的结合效率与观察到的 MCF-7 细胞毒性之间存在良好的相关性。这支持在开发乳腺癌特异性药物中使用该模型。
