与β -丙氨酸配体配合的dihenium (III):抗癌、抗氧化和dna结合特性

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摘要

先前我们已经证明,与先前研究的烷基羧酸复合物相比,二羧酸二代迪henium(III)与γ-氨基丁酸复合物具有更高的抗肿瘤活性,也可能作为顺铂作用机制的调节剂和肿瘤生物体中红细胞的稳定剂。因此,本工作的任务是在体内肿瘤生长模型中研究络合物顺式-[Re2(β-Ala)2Cl6] (I)的抗癌活性,并了解氨基酸残基是否影响簇铼(III)化合物氨基酸衍生物的dna结合活性。利用Wistar大鼠接种肿瘤细胞,研究了复合物I的抗肿瘤特性。单独以游离和脂质体形式引入的化合物分别抑制肿瘤生长36%和45%,这比具有烷基配体的dihenium (III)簇更有效。I和顺铂联合引入对肿瘤生长有显著影响,大多数动物的肿瘤消失。牛胸腺DNA (CT-DNA)的电子吸收光谱在i的添加量增加时表现出高色度。~ 260 nm处的DNA波段是由核酸碱基的π-π*跃迁引起的,该特征波段的强度变化和轻微的波长变化反映了DNA相应的结构修饰,包括堆积的变化。互补链之间氢键的破坏,DNA碱基的共价结合,芳香环的嵌入等等。得到了与CT-DNA的结合常数Kb(I) = 2.43 × 103 M-1,该值低于经典DNA插入物的报道值,与其他dihenium (III)配合物的结合常数的大小相当;用cisPt和过氧化氢滴定СT-DNA也会导致异色效应,低浓度时较弱,高浓度时更明显;当使用H2O2或顺铂时,DNA结合常数增加了数倍,证实了肿瘤细胞中I与DNA相互作用的氧化还原激活机制。研究结果表明,dihenium (III)簇的氨基酸衍生物在抗肿瘤治疗中的应用是可能的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dirhenium(III) complex with beta-alanine ligand: anticancer, antioxidant and DNA-binding properties
Earlier we have shown that dirhenium(III) dicarboxylate complex with γ-aminobutyric acid possessed higher antitumor activity, than those of the previously investigated alkylcarboxylates, also may act as a modulator of cisplatin mechanism of action and as a stabilizer of red blood cells in tumor-bearing organisms. Thus, the task of the work was to investigate anticancer activity of the complex cis-[Re2(β-Ala)2Cl6] (I) in the model of tumor growth in vivo and to realize if the amino acid residue influences the DNA-binding activity of the amino acid derivatives of the cluster rhenium(III) compounds. Antitumor properties of the complex I were studied in the model of tumor growth with the use of Wistar rats inoculated by tumor carcinoma Guerink cells. The introduction of the compound alone in free and liposomal forms inhibited the tumor growth by 36 % and 45 % correspondingly, that is more than for dirhenium(III) clusters with alkyl ligands. The combined introduction of I and cisplatin had a significant impact on the tumor growth and showed the disappearance of the tumors in most of the animals. No considerable differences were found between introduction of liposomal and free form of I. The electronic absorption spectra of Calf Thymus DNA (CT-DNA) exhibit hyperchromism in the presence of increasing amounts of I. The DNA band at ~ 260 nm arises from the π-π* transitions of the nucleic acid bases and changes in the intensity and slight wavelength shifts of this characteristic band reflect the corresponding structural modifications of the DNA, which include changes in stacking, disruption of the hydrogen bonds between complementary strands, covalent binding of the DNA bases, intercalation of aromatic rings and others. The binding constant Kb(I) = 2.43 × 103 M-1 to CT-DNA was obtained that was lower than the values reported for the classical DNA intercalators and compares well with the magnitude of the binding constants for other complexes of dirhenium(III); titration of СT-DNA with cisPt and hydrogen peroxide also leads to a hypochromic effect, weak at low concentrations and more significant at high concentrations of I; the DNA binding constants increased in several times when using H2O2 or cisplatin that confirms a mechanism for redox activation of interaction of I with DNA in a cancer cell. The obtained results demonstrate the possibility of application of the amino acid derivatives of dirhenium(III) clusters in antitumor therapy.
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