Kubešová Kateřina, Trávníček Zdeněk, Dvořák Zdeněk
Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Slechtitelu 27, CZ-783 71, Olomouc, Czech Republic.
Department of Inorganic Chemistry, Faculty of Science, Palacký University, Tr.17.listopadu 12, CZ-771 46, Olomouc, Czech Republic.
Eur J Med Chem. 2016 Oct 4;121:530-540. doi: 10.1016/j.ejmech.2016.05.064. Epub 2016 Jun 6.
Development of metal-based compounds is an important research avenue in anti-cancer and anti-inflammatory drug discovery. Here we examined the effects of three gold (I) mixed-ligand complexes with the general formula [Au(Ln)(PPh3)] (1, 2, 3) involving triphenylphosphine (PPh3) and a deprotonated form of O-substituted derivatives of 9-deazahypoxanthine (Ln) on the transcriptional activity of aryl hydrocarbon receptor (AhR), androgen receptor (AR), glucocorticoid receptor (GR), thyroid receptor (TR), pregnane X receptor (PXR) and vitamin D receptor (VDR), employing gene reporter assays. In addition, we measured mRNA (RT-PCR) and protein (western blot) expression of target genes for those receptors, including drug-metabolizing P450s, in primary human hepatocytes and cancer cell lines LS180 and HepG2. The tested compounds displayed anti-glucocorticoid effects, as revealed by inhibition of dexamethasone-inducible transcriptional activity of GR and down-regulation of tyrosine aminotransferase. All the compounds slightly and dose-dependently activated PXR and AhR, and moderately induced CYP3A4 and CYP1A1/2 genes in human hepatocytes and LS180 cells. The complexes antagonized basal and ligand-activated AR and VDR, indicating inverse agonist behaviour. Both basal and thyroid hormone-inducible transcriptional activity of TR was dose-dependently increased by all tested compounds. In contrast, the expression of SPOT14 mRNA was decreased by tested compounds in human hepatocytes and HepG2 cells. In conclusion, if intended for human pharmacotherapy, the potential of the complexes 1-3 to influence studied receptors should be taken in account.
金属基化合物的开发是抗癌和抗炎药物发现中的一个重要研究方向。在此，我们使用基因报告分析方法，研究了三种通式为[Au(Ln)(PPh3)]（1、2、3）的金（I）混合配体配合物的作用，这些配合物涉及三苯基膦（PPh3）以及9-脱氮次黄嘌呤的O-取代衍生物的去质子化形式（Ln），对芳烃受体（AhR）、雄激素受体（AR）、糖皮质激素受体（GR）、甲状腺受体（TR）、孕烷X受体（PXR）和维生素D受体（VDR）转录活性的影响。此外，我们还检测了原代人肝细胞以及癌细胞系LS180和HepG2中这些受体的靶基因的mRNA（逆转录聚合酶链反应）和蛋白质（蛋白质免疫印迹）表达，这些靶基因包括药物代谢性细胞色素P450。所测试的化合物表现出抗糖皮质激素作用，这通过抑制地塞米松诱导的GR转录活性以及酪氨酸转氨酶的下调得以揭示。所有化合物均轻微且呈剂量依赖性地激活PXR和AhR，并在人肝细胞和LS180细胞中适度诱导CYP3A4和CYP1A1/2基因。这些配合物拮抗基础状态和配体激活的AR和VDR，表明具有反向激动剂行为。所有测试化合物均使TR的基础状态和甲状腺激素诱导的转录活性呈剂量依赖性增加。相反，测试化合物在人肝细胞和HepG2细胞中降低了SPOT14 mRNA的表达。总之，如果用于人类药物治疗，应考虑配合物1 - 3影响所研究受体的可能性。
