School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
J Inorg Biochem. 2017 Dec;177:395-401. doi: 10.1016/j.jinorgbio.2017.08.034. Epub 2017 Sep 4.
Ru(II) and Os(II) complexes of 2-pyridinecarbothioamide ligands were introduced as orally administrable anticancer agents (S.M. Meier, M. Hanif, Z. Adhireksan, V. Pichler, M. Novak, E. Jirkovsky, M.A. Jakupec, V.B. Arion, C.A. Davey, B.K. Keppler, C.G. Hartinger, Chem. Sci., 2013, 4, 1837-1846). In order to identify structure-activity relationships, a series of N-phenyl substituted pyridine-2-carbothiamides (PCAs) were obtained by systematically varying the substituents at the phenyl ring. The PCAs were then converted to their corresponding Ru(η-p-cymene) complexes and characterized spectroscopically and by X-ray diffraction as well as in terms of stability in water and HCl. The cytotoxic activity of the PCA ligands and their respective organoruthenium compounds was evaluated in a panel of cell lines (HCT116, H460, SiHa and SW480). The lipophilic PCAs 1-4 showed cytotoxicity in the low micromolar range and 6 was the most potent compound of the series with an IC value of 1.1μM against HCT116 colon cancer cells. These observations were correlated with calculated octanol/water partition coefficient (clogP) data and quantitative estimated druglikeness. A similar trend as for the PCAs was found in their Ru complexes, where the complexes with more lipophilic ligands proved to be more cytotoxic in all tested cell lines. In general, the PCAs and their organoruthenium derivatives demonstrated excellent drug-likeness and cytotoxicity with IC values in the low micromolar range, making them interesting candidates for further development as orally active anticancer agents.
将钌（II）和锇（II）配合物的 2-吡啶甲硫酰胺配体作为可口服的抗癌药物进行了介绍（S.M. Meier、M. Hanif、Z. Adhireksan、V. Pichler、M. Novak、E. Jirkovsky、M.A. Jakupec、V.B. Arion、C.A. Davey、B.K. Keppler、C.G. Hartinger，Chem. Sci.，2013，4，1837-1846）。为了确定结构-活性关系，通过系统地改变苯环上的取代基，获得了一系列 N-苯基取代的吡啶-2-甲硫酰胺（PCAs）。然后，将 PCAs 转化为其相应的 Ru(η-p-cymene)配合物，并通过光谱学、X 射线衍射以及在水中和 HCl 中的稳定性进行了表征。在一系列细胞系（HCT116、H460、SiHa 和 SW480）中评估了 PCA 配体及其相应的有机钌化合物的细胞毒性。亲脂性 PCAs 1-4 在低微摩尔范围内具有细胞毒性，而 6 是该系列中最有效的化合物，对 HCT116 结肠癌细胞的 IC 值为 1.1μM。这些观察结果与计算的辛醇/水分配系数（clogP）数据和定量估计的药物相似性相关。在其 Ru 配合物中也发现了与 PCAs 相似的趋势，其中具有更亲脂性配体的配合物在所有测试的细胞系中均显示出更高的细胞毒性。一般来说，PCAs 及其有机钌衍生物表现出良好的药物相似性和细胞毒性，IC 值在低微摩尔范围内，使它们成为进一步开发作为口服活性抗癌药物的有前途的候选物。
