Discovery of high in vitro and in vivo antitumor activities of organometallic ruthenium(II)-arene complexes with 5,7-dihalogenated-2-methyl-8-quinolinol.
Discovery of high in vitro and in vivo antitumor activities of organometallic ruthenium(II)-arene complexes with 5,7-dihalogenated-2-methyl-8-quinolinol.
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发现有机金属钌 (II)-芳烃与 5,7-二卤代-2-甲基-8-羟基喹啉配合物具有高体外和体内抗肿瘤活性。
DOI：
10.1039/c9dt00866g
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发表时间：
2019
影响因子：
4
通讯作者：
Fu-Pei Liang
中科院分区：
文献类型：
--
作者：
Ting Meng;Qi-Pin Qin;Zi-Lu Chen;Hua-Hong Zou;Kai Wang;Fu-Pei Liang
本文报道了13种金属有机钌（II）-芳烃配合物的合成、结构表征和抗癌性能：[茹（η6-对伞花烃）Cl-（L1）]（1），[Ru（η6-对伞花烃）Cl-（L2）]（2），[Ru（η6-对伞花烃）Cl-（L3）]（3），[Ru（η6-对伞花烃）Cl-（L4）]（4），[Ru（η6-对伞花烃）Cl-（L5）]（5），[Ru（η6-对伞花烃）I-（L1）]（6）、[Ru（η6-对伞花烃）I-（L2）]（7）、[Ru（η6-对伞花烃）I-（L3）]（8）、[Ru（η6-对伞花烃）I-（L4）]（9）、[Ru（η6-对伞花烃）I-（L5）]（10）、[Ru（η6-对伞花烃）I-（L 6）]（11）、[Ru（η6-对伞花烃）I-（L7）]（12）和[Ru（η6-对伞花烃）Cl-（L 8）]（13）分别含有去质子化的5，7-二氯-2-甲基-8-羟基喹啉（H-L1）、5，7-二溴-2-甲基-8-羟基喹啉（H-L2）、5-氯-7-碘-8-羟基-喹啉（H-L3）、5，7-二溴-8-羟基喹啉（H-L4）、5，7-二碘-8-羟基喹啉（H-L5）、8-羟基-2-甲基喹啉（H-L 6）、2，8-喹啉二醇（H-L7）或6，7-二氯-5，8-喹啉二酮（H-L 8）。MTT（3-（4，5-dimethylthiazol-2-yl）-2，5-diphenyltetrazolium bromide）比色法显示13个钌（II）芳烃配合物1-13对HeLa细胞的选择性高于正常HL-7702细胞。此外，含有活性配体H-L1和H-L2的1、2、5和6显示出显著的细胞毒性，对HeLa癌细胞的IC 50值分别为2.00 ± 0.20 nM、0.89 ± 0.62 μM、25.00 ± 0.30 nM和2.18 ± 0.35 μM。这些值表明比6，7-二氯-5，8-喹啉二酮和其它8-羟基喹啉衍生物Ru（II）-芳烃配合物更高的活性。有趣的是，所有这些Ru（II）-芳烃配合物1-13对人肝（HL-7702）细胞的毒性均显着降低。此外，1和2诱导HeLa细胞凋亡是通过抑制端粒酶活性和线粒体功能障碍介导的，并导致DNA损伤和增强HeLa细胞的抗迁移活性。有机金属Ru（II）-芳烃配合物1的抗肿瘤活性明显优于有机金属Ru（II）-芳烃配合物2，这与有机金属Ru（II）-芳烃配合物1的L1配体中5，7-二氯取代基的关键作用密切相关。值得注意的是，1在体内显示出比顺铂更高的对人宫颈细胞（HeLa）的异种移植肿瘤生长的抑制活性（肿瘤生长抑制率（TGIR）= 58.5%）。本研究首次证明了5，7-二卤代-2-甲基-8-羟基喹啉类金属有机钌（II）-芳烃配合物1和2是新的钌（II）抗癌药物候选物。
This paper reports the synthesis, structure characterization, and anticancer properties of 13 organometallic Ru(II)–arene complexes: [Ru(η6-p-cymene)Cl-(L1)] (1), [Ru(η6-p-cymene)Cl-(L2)] (2), [Ru(η6-p-cymene)Cl-(L3)] (3), [Ru(η6-p-cymene)Cl-(L4)] (4), [Ru(η6-p-cymene)Cl-(L5)] (5), [Ru(η6-p-cymene)I-(L1)] (6), [Ru(η6-p-cymene)I-(L2)] (7), [Ru(η6-p-cymene)I-(L3)] (8), [Ru(η6-p-cymene)I-(L4)] (9), [Ru(η6-p-cymene)I-(L5)] (10), [Ru(η6-p-cymene)I-(L6)] (11), [Ru(η6-p-cymene)I-(L7)] (12), and [Ru(η6-p-cymene)Cl-(L8)] (13) respectively containing deprotonated 5,7-dichloro-2-methyl-8-quinolinol (H-L1), 5,7-dibromo-2-methyl-8-quinolinol (H-L2), 5-chloro-7-iodo-8-hydroxy-quinoline (H-L3), 5,7-dibromo-8-quinolinol (H-L4), 5,7-diiodo-8-hydroxyquinoline (H-L5), 8-hydroxy-2-methylquinoline (H-L6), 2,8-quinolinediol (H-L7), or 6,7-dichloro-5,8-quinolinedione (H-L8). MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that 13 organometallic Ru(II)–arene complexes 1–13 are more selective for HeLa cells than normal HL-7702 cells. In addition, 1, 2, 5, and 6, which contain the active ligands H-L1 and H-L2, showed remarkable cell cytotoxicity, giving the respective IC50 values of 2.00 ± 0.20 nM, 0.89 ± 0.62 μM, 25.00 ± 0.30 nM, and 2.18 ± 0.35 μM on HeLa cancer cells. These values indicated higher activity than 6,7-dichloro-5,8-quinolinedione and other 8-hydroxyquinoline derivative Ru(II)–arene complexes. Interestingly, all these Ru(II)–arene complexes 1–13 were significantly less toxic to human hepatic (HL-7702) cells. Moreover, 1- and 2-induced HeLa cell apoptosis was mediated by the inhibition of telomerase activity and dysfunction of mitochondria, and resulted in DNA damage and increased anti-migration activity on HeLa cells. The organometallic Ru(II)–arene complex 1 exhibited evident priority to the antitumor activity compared to 2, which should be highly associated with the key roles of the 5,7-dichloro substituted groups in the L1 ligand of organometallic Ru(II)–arene complexes 1. Remarkably, 1 showed higher inhibitory activity against the xenograft tumor growth of human cervical cells (HeLa) in vivo (tumor growth inhibition rate (TGIR) = 58.5%) than cisplatin. This study was the first to show that the 5,7-dihalogenated-2-methyl-8-quinolinol organometallic Ru(II)–arene complexes 1 and 2 are novel Ru(II) anticancer drug candidates.