Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, PR China.
Dalton Trans. 2022 Mar 15;51(11):4447-4457. doi: 10.1039/d1dt03856g.
We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) Ru arene complexes 1-8 of [(η-arene)Ru(R-SO-EnBz)X], where the arene is benzene, HO(CH)O-phenyl or biphenyl (biph), X = Cl or I, and R is phenyl, 4-Me-phenyl, 4-NO-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η-biph)Ru(4-Me-phenyl-SO-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1-8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC values ranging from 4.1 to >50 μM, although, remarkably, complex 7 [(η-biph)Ru(phenyl-SO-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5-9.7 h. The complexes reacted rapidly with the thiols glutathione (GSH) and -acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η-biph)Ru(GS)] or [(η-biph)Ru(NAC-H)], with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η-biph)Ru(4-Me-phenyl-SO-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex.
我们合成了一系列新型取代的磺酰基乙二胺（en）钌芳烃配合物 1-8，它们是[(η-芳烃)Ru(R-SO-EnBz)X]，其中芳烃是苯、HO(CH)O-苯基或联苯（biph），X = Cl 或 I，R 是苯基、4-Me-苯基、4-NO-苯基或丹磺酰基。配合物 3 的“钢琴凳”结构，[(η-biph)Ru(4-Me-phenyl-SO-EnBz)I]，通过 X 射线晶体学得到证实。其水合产物的值被确定为高（9.1 至 9.7）。配合物 1-8 对人 A2780 卵巢和 A549 肺癌细胞具有抗增殖活性，IC 值范围为 4.1 至 >50 μM，尽管值得注意的是，配合物 7 [(η-biph)Ru(phenyl-SO-EnBz)Cl]对 A2780 细胞没有活性，但对 A549 细胞的活性与临床药物顺铂相当。所有这些配合物在以甲酸钠为氢供体的转移氢化（TH）中将 NAD 转化为 NADH 中也表现出催化活性，TOF 范围为 2.5-9.7 h。这些配合物与谷胱甘肽（GSH）和 -乙酰-L-半胱氨酸（NAC）迅速反应，形成双核桥联配合物[(η-biph)Ru(GS)]或[(η-biph)Ru(NAC-H)]，同时检测到释放出的二胺配体通过 LC-MS。此外，在水溶液中配合物 8 的荧光的开启证实了在与这些硫醇的反应中螯合的 DsEnBz 配体的释放。与 GSH 的反应由于配合物的分解而阻碍了 NAD 向 NADH 的催化 TH。当将配合物 2 [(η-biph)Ru(4-Me-phenyl-SO-EnBz)Cl]与 L-丁硫氨酸亚砜（L-BSO）一起给药到细胞中时，L-BSO 是 GSH 合成的抑制剂，部分恢复了对 A2780 卵巢癌细胞的抗癌活性。配合物 2 引起浓度依赖性的 G1 期细胞周期停滞，并在 A2780 人卵巢癌细胞中诱导产生显著水平的活性氧（ROS）。诱导的 ROS 量随 GSH 浓度的增加而减少，这可能是由于形成双核 Ru-SG 配合物所致。
