Developing Anticancer Copper(II) Pro-drugs Based on the Nature of Cancer Cells and the Human Serum Albumin Carrier IIA Subdomain
Developing Anticancer Copper(II) Pro-drugs Based on the Nature of Cancer Cells and the Human Serum Albumin Carrier IIA Subdomain
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根据癌细胞的性质和人血清白蛋白载体 IIA 子域开发抗癌铜 (II) 前药。
DOI：
10.1021/acs.molpharmaceut.5b00314
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发表时间：
2015-10-01
影响因子：
4.9
通讯作者：
Liang, Hong
中科院分区：
文献类型：
--
作者：
Gou, Yi;Qi, Jinxu;Liang, Hong
为了协同增强抗癌铜药物的选择性和效率，我们基于人血清白蛋白（HSA）IIA亚结构域和癌细胞的性质，提出并建立了开发抗癌铜前药的模型。在吡啶、咪唑或吲唑配体存在下，合成了 2-羟基-1-萘醛苯甲酰腙席夫碱配体的三种铜（II）化合物（C1-C3）。三种 HSA 复合物的结构表明，Cu 化合物与 HSA IIA 子结构域中的疏水空腔结合。其中，C1和C2的吡啶和咪唑配体被Lys199取代，His242直接与Cu(II)配位。 C3 的吲唑和 Br 配体分别被 Lys199 和 His242 取代。与单独的Cu(II)化合物相比，HSA复合物可增强MCF-7细胞中的细胞毒性约3-5倍，但在体外不会通过在癌细胞中选择性积累而在一定程度上提高在正常细胞中的细胞毒性水平。我们发现HSA复合物通过靶向细胞周期蛋白依赖性激酶1（CDK1）并下调CDK1和细胞周期蛋白B1的表达，在MCF-7的G2/M期具有更强的细胞周期阻滞能力。此外，HSA复合物可能通过内在活性氧（ROS）介导的线粒体途径促进MCF-7细胞凋亡，并伴有Bcl-2家族蛋白的调节。
To synergistically enhance the selectivity and efficiency of anticancer copper drugs, we proposed and built a model to develop anticancer copper pro-drugs based on the nature of human serum albumin (HSA) IIA subdomain and cancer cells. Three copper(II) compounds of a 2-hydroxy-1-naphthaldehyde benzoyl hydrazone Schiff-base ligand in the presence pyridine, imidazole, or indazole ligands were synthesized (C1-C3). The structures of three HSA complexes revealed that the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. Among them, the pyridine and imidazole ligands of C1 and C2 are replaced by Lys199, and His242 directly coordinates with Cu(II). The indazole and Br ligands of C3 are replaced by Lys199 and His242, respectively. Compared with the Cu(II) compounds alone, the HSA complexes enhance cytotoxicity in MCF-7 cells approximately 3-5-fold, but do not raise cytotoxicity levels in normal cells in vitro through selectively accumulating in cancer cells to some extent. We find that the HSA complex has a stronger capacity for cell cycle arrest in the G2/M phase of MCF-7 by targeting cyclin-dependent kinase 1 (CDK1) and down-regulating the expression of CDK1 and cyclin B1. Moreover, the HSA complex promotes MCF-7 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.