半三明治式的铑配合物,以茜素为抗癌药物:体内外研究。
"Half-Sandwich" Ruthenium Complexes with Alizarin as Anticancer Agents: In Vitro and In Vivo Studies.
发表日期:2023 Apr 26
作者:
João Honorato de Araujo-Neto, Adriana P M Guedes, Celisnolia M Leite, Carlos André F Moraes, Andressa L Santos, Rafaella da S Brito, Thiago L Rocha, Francyelli Mello-Andrade, Javier Ellena, Alzir A Batista
来源:
Cellular & Molecular Immunology
摘要:
在研究瑞铂/芳香族物质与蒽醌茜素(L)化学结合的过程中,利用光谱技术(质谱、红外和1D/2D NMR)、摩尔电导率、元素分析和X射线衍射表征了三个具有通式[Ru(L)Cl(η6-p-cymene)] (C1)、[Ru(L)(η6-p-cymene)(PPh3)]PF6 (C2)和[Ru(L)(η6-p-cymene)(PEt3)]PF6 (C3)的新配合物。C1 显示出荧光性,类似于自由蒽醌,而在 C2 和 C3 中,荧光发射可能被单膦磷熄灭,晶体结构数据显示疏水相互作用在分子间的结合中占主导地位。在MDA-MB-231(三重阴性乳腺癌)、MCF-7(乳腺癌)和A549(肺癌)肿瘤细胞系及MCF-10A(乳腺)和MRC-5(肺)非肿瘤细胞系中评估了配合物的细胞毒性。C1 和C2 配合物对乳腺肿瘤细胞系更具选择性,其中C2 的细胞毒性最强(MDA-MB-231 的IC50 值为6.5μM) 。此外,化合物C1 与DNA 发生共价作用,而C2 和C3则只有弱的相互作用;然而细胞自流式细胞术和共聚焦显微镜的内化研究表明,C1 配合物不会在活细胞中累积,只有在细胞穿透后才能在细胞质中检测到。综合研究这些配合物的作用机理,发现C2 能促使MDA-MB-231 细胞周期停滞在亚 G1 期,抑制其集落形成,具有可能的抗转移作用,在伤口愈合实验中也能阻止细胞迁移(24小时内伤口愈合率为13%)。斑马鱼的体内毒理学实验证明,C1 和C3 显示出最强的幼鱼胚胎发育毒性(抑制自发运动和心跳),而C2,在体内临床前筛选中展现了最低的毒性,是最有前途的抗癌药物。
Upon exploration of the chemistry of the combination of ruthenium/arene with anthraquinone alizarin (L), three new complexes with the general formulas [Ru(L)Cl(η6-p-cymene)] (C1), [Ru(L)(η6-p-cymene)(PPh3)]PF6 (C2), and [Ru(L)(η6-p-cymene)(PEt3)]PF6 (C3) were synthesized and characterized using spectroscopic techniques (mass, IR, and 1D and 2D NMR), molar conductivity, elemental analysis, and X-ray diffraction. Complex C1 exhibited fluorescence, such as free alizarin, while in C2 and C3, the emission was probably quenched by monophosphines and the crystallographic data showed that hydrophobic interactions are predominant in intermolecular contacts. The cytotoxicity of the complexes was evaluated in the MDA-MB-231 (triple-negative breast cancer), MCF-7 (breast cancer), and A549 (lung) tumor cell lines and MCF-10A (breast) and MRC-5 (lung) nontumor cell lines. Complexes C1 and C2 were more selective to the breast tumor cell lines, and C2 was the most cytotoxic (IC50 = 6.5 μM for MDA-MB-231). In addition, compound C1 performs a covalent interaction with DNA, while C2 and C3 present only weak interactions; however, internalization studies by flow cytometry and confocal microscopy showed that complex C1 does not accumulate in viable MDA-MB-231 cells and is detected in the cytoplasm only after cell permeabilization. Investigations of the mechanism of action of the complexes indicate that C2 promotes cell cycle arrest in the Sub-G1 phase in MDA-MB-231, inhibits its colony formation, and has a possible antimetastatic action, impeding cell migration in the wound-healing experiment (13% of wound healing in 24 h). The in vivo toxicological experiments with zebrafish indicate that C1 and C3 exhibit the most zebrafish embryo developmental toxicity (inhibition of spontaneous movements and heartbeats), while C2, the most promising anticancer drug in the in vitro preclinical tests, revealed the lowest toxicity in in vivo preclinical screening.