Baker Jennifer R, Pollard Brett L, Lin Andrew J S, Gilbert Jayne, Paula Stefan, Zhu Xiao, Sakoff Jennette A, McCluskey Adam
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. 2021 May 6;16(9):1499-1512. doi: 10.1002/cmdc.202000721. Epub 2021 Feb 25.
To exploit the interaction of the aryl hydrocarbon receptor (AhR) pathway in developing breast-cancer-specific cytotoxic compounds, we examined the breast cancer selectivity and the docking pose of the AhR ligands (Z)-2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (NAP-6; 5) and 10-chloro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ; 6). While the breast cancer selectivity of 5 in vitro is known, we discuss the SAR around this lead and, by using phenotypic cell-line screening and the MTT assay, show for the first time that 6 also presents with breast cancer selectivity, notably in the triple-negative (TN) receptor breast cancer cell line MDA-MB-468, the ER+ breast cancer cell lines T47D, ZR-75-1 and the HER2+ breast cancer cell line SKBR3 (GI values of 0.098, 0.97, 0.13 and 0.21 μM, respectively). Indeed, 6 is 55 times more potent in MDA-MB-468 cells than normal MCF10A breast cells (GI of 0.098 vs 5.4 μM) and more than 130 times more potent than in cell lines derived from pancreas, brain and prostate (GI of 0.098 vs 10-13 μM). Molecular docking poses of 5 and 6 together with analogue synthesis and phenotypic screening show the importance of the naphthalene moiety, and an ortho-disposed substituent on the N-phenyl moiety for biological activity.
为了开发在乳腺癌中具有特异性细胞毒性的化合物与芳烃受体（AhR）途径之间的相互作用，我们研究了AhR配体（Z）-2-（2-氨基苯基）-1H-苯并[de]异喹啉-1,3（2H）-二酮（NAP-6；5）和10-氯-7H-苯并[de]苯并[4,5]咪唑并[2,1-a]异喹啉-7-酮（10-Cl-BBQ；6）的乳腺癌选择性和对接构象。虽然5在体外的乳腺癌选择性是已知的，但我们讨论了围绕该先导化合物的构效关系，并通过表型细胞系筛选和MTT试验，首次表明6也具有乳腺癌选择性，特别是在三阴性（TN）受体乳腺癌细胞系MDA-MB-468、雌激素受体阳性（ER+）乳腺癌细胞系T47D、ZR-75-1以及人表皮生长因子受体2阳性（HER2+）乳腺癌细胞系SKBR3中（GI值分别为0.098、0.97、0.13和0.21 μM）。事实上，6在MDA-MB-468细胞中的活性比正常MCF10A乳腺细胞高55倍（GI分别为0.098 μM和5.4 μM），比源自胰腺、脑和前列腺的细胞系高130倍以上（GI分别为0.098 μM和10 - 13 μM）。5和6的分子对接构象以及类似物合成和表型筛选表明萘部分以及N-苯基部分上的邻位取代基对生物活性的重要性。
