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Copper(II) and iron(III) complexes of chiral dehydroabietic acid derived from natural rosin: metal effect on structure and cytotoxicity.
Metallomics ( IF 3.4 ) Pub Date : 2021-04-24 , DOI: 10.1093/mtomcs/mfab014
Bao-Li Fei,Chun-Nuan Hui,Zuzhuang Wei,Ling-Yan Kong,Jian-Ying Long,Chunhua Qiao,Zhen-Feng Chen

A novel optically pure dinuclear copper(II) complex of a rosin derivative dehydroabietic acid (DHA, HL) was synthesized and fully characterized. The in vitro antitumor activities of the copper(II) complex Cu2(µ2-O)(L)4(DMF)2 (1) were explored and compared with those of a trinuclear iron(III) complex [Fe3(µ3-O)(L)6(CH3OH)2(CH3O)]·H2O (2). 1 was more cytotoxic than 2, and the in vitro cytotoxicity of 1 was comparable to that of cisplatin and oxaliplatin. The metal coordination improved the cytotoxicity of DHA. 1 could arrest cycle in G1 phase and induce apoptosis in MCF-7 cell. 1 increased reactive oxygen species level, GSSG/GSH ratio, and Ca2+ production, and caused the loss of mitochondrial membrane potential (Δψm) in MCF-7 cells. The up-regulated Bax and down-regulated Bcl-2 expression levels, caspase-9/caspase-3 activation, and the release of Cyt c demonstrate that 1 triggered mitochondria-mediated intrinsic apoptosis in MCF-7 cells. Caspase-8/caspase-4 activation and up-regulated Fas expression indicate that death receptor-mediated extrinsic apoptosis was included. Comet assay and up-regulated γ-H2AX and p53 expressions confirmed that 1 caused DNA damage in MCF-7 cells. Moreover, 1 led to enhancement of the biomarker of lipid peroxidation and the indicator of protein carbonylation in MCF-7 cells. All the results suggest that 1 could kill MCF-7 cells by generating oxidative stress, impairing DNA, promoting lipid peroxidation and protein carbonylation, and inducing apoptosis and autophagy. Furthermore, 1 also displayed antimetastatic activities with inhibition of cell invasion and migration, together with antiangiogenesis properties. On the whole, copper complex based on rosin derivatives is worth developing as metal-based antitumor drugs.

中文翻译:

源自天然松香的手性脱氢松香酸的铜 (II) 和铁 (III) 配合物:金属对结构和细胞毒性的影响。

合成并充分表征了松香衍生物脱氢松香酸(DHA,HL)的新型光学纯双核铜(II)配合物。探索了铜 (II) 配合物 Cu2(µ2-O)(L)4(DMF)2 (1) 的体外抗肿瘤活性,并与三核铁 (III) 配合物 [Fe3(µ3-O) (L)6(CH3OH)2(CH3O)]·H2O(2)。1的细胞毒性大于2,1的体外细胞毒性与顺铂和奥沙利铂相当。金属配位提高了 DHA 的细胞毒性。1可以在G1期阻滞周期并诱导MCF-7细胞凋亡。1 增加活性氧水平、GSSG/GSH 比率和 Ca2+ 产生,并导致 MCF-7 细胞中线粒体膜电位 (Δψm) 的丧失。上调 Bax 和下调 Bcl-2 表达水平,caspase-9/caspase-3 激活,Cyt c 的释放表明 1 在 MCF-7 细胞中触发了线粒体介导的内在细胞凋亡。Caspase-8/caspase-4 激活和 Fas 表达上调表明死亡受体介导的外在细胞凋亡包括在内。彗星试验和上调 γ-H2AX 和 p53 表达证实 1 在 MCF-7 细胞中引起 DNA 损伤。此外,1导致MCF-7细胞中脂质过氧化的生物标志物和蛋白质羰基化指标的增强。所有结果表明1可以通过产生氧化应激、损伤DNA、促进脂质过氧化和蛋白质羰基化、诱导细胞凋亡和自噬来杀死MCF-7细胞。此外,1 还显示出抗转移活性,抑制细胞侵袭和迁移,以及抗血管生成特性。总体上,
更新日期:2021-04-24
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