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Effects of structurally varied fluorescent half-sandwich iridium(III) Schiff base complexes on A549 cell line 不同结构的荧光半夹心铱席夫碱配合物对A549细胞系的影响
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-26 DOI: 10.1016/j.jinorgbio.2024.112792
Xicheng Liu, Changjian Ji, Rui Tao, Wenya Zheng, Mengxian Liu, Shiqing Bi, Qinghua Chang, Xiang-Ai Yuan, Mingbo Yue, Zhe Liu
Half-sandwich iridium(III) (IrIII) anticancer complexes, as promising alternatives to platinum-based drugs, especially for solving resistance to platinum drugs, have demonstrated excellent application prospect. The potency of these IrIII complexes as anticancer agents could be significantly enhanced through the strategic modification of their peripheral ligands. In this study, four structurally varied triphenylamine (TPA)-modified half-sandwich IrIII Schiff base complexes were designed and prepared. The incorporation of TPA unit has effectively endowed these complexes with suitable emission, which facilitates the evaluation of intracellular accumulation and cell morphology. These complexes demonstrated favorable in vitro anti-proliferative activity against A549 cell line (lung cancer cells, derived from alveolar basal epithelial cells), especially for pentamethylcyclopentadiene (Cp*)-based one (IrTS1 and IrTS3), and that is almost 2.5-fold more than cisplatin under the same conditions. Meanwhile, IrTS1 and IrTS3 possessed excellent activity against A549/DDP (cisplatin-resistant) cell line and the similar cytotoxicity to cisplatin against BEAS-2B cell line (derived from the bronchial epithelium of normal human lungs), then following a mitochondria apoptotic channel.
半夹层铱(III) (IrIII)抗癌配合物作为铂基药物的有希望的替代品,特别是在解决铂类药物耐药方面,显示出良好的应用前景。通过对其外周配体进行战略性修饰,可以显著增强这些IrIII配合物作为抗癌药物的效力。本研究设计并制备了四种结构各异的三苯胺(TPA)修饰的半夹心IrIII席夫碱配合物。TPA单元的加入有效地赋予了这些复合物合适的发射能力,便于对细胞内积累和细胞形态的评价。这些复合物对A549细胞系(来源于肺泡基底上皮细胞的肺癌细胞)具有良好的体外抗增殖活性,特别是对五甲基环戊二烯(Cp*)为基础的复合物(IrTS1和IrTS3),在相同条件下,其抗增殖活性几乎是顺铂的2.5倍。同时,IrTS1和IrTS3对A549/DDP(顺铂耐药)细胞系具有良好的活性,对BEAS-2B细胞系(来源于正常人肺支气管上皮)具有与顺铂相似的细胞毒性,并遵循线粒体凋亡通道。
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引用次数: 0
Positively-charged, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes functionalized with ethacrynic acid: Synthesis, characterizaion, and antitumor effect 带正电的查尔酮-羟吡啶杂化钌(II)-芳烃配合物的合成、表征及抗肿瘤作用
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-22 DOI: 10.1016/j.jinorgbio.2024.112778
Yuxin Xuan , Yuxi Yan , Xiaonan Wei, Shuxiang Wang, Jinchao Zhang, Yonghe Tang, Shenghui Li
A new family of ethacrynic acid-functionalized, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes (4a-4e) have been designed, synthesis and fully characterized by 1H and 13C NMR, ESI-MS, elemental analysis, and melting point tests. The molecular structure of 3a, one of the precursor complexes, has been determined by single-crystal X-ray diffraction. The cytotoxicity of the obtained complexes toward human cancer cell lines such as HeLa, MGC803, A549, MDA-MB-231, and MCF-7 cells have been investigated by MTT assay. Whereas complexes 4d and 4e showed significantly higher cytotoxicity than cisplatin (the positive control group) and complexes 3a-3e. Moreover, complexes 4d and 4e exhibited a certain selectivity (selectivity index: 7.33 and 7.57) toward MCF-7 cells over MCF-10a normal cells. Glutathione S-transferases (GSTs) activity assay indicate that complexes 4d and 4e exhibited higher GST inhibitory activity than ethacrynic acid (EA, the best characterized GST inhibitor), consistent with their higher cytotoxicity. Further mechanistic studies showed that 4e-induced cell apoptosis may be aroused by the production of ROS, the loss of mitochondrial membrane potential and G2/M phase cell arrest in MCF-7 cells. In addition, the in vivo antitumor effect study on the xenograft mouse models of MCF-7 cells reveal that complex 4e significantly inhibited tumor growth with a higher inhibition efficiency of 68.80 %, in comparison with the groups treated with cisplatin (59.25 %). These results highlight the strong possibility to develop positively-charged, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes funcionalized with GST inhibitor as promising anticancer agents.
设计、合成了一类新的乙炔酸功能化的查尔酮-羟基吡啶杂化钌(II)-芳烃配合物(4a-4e),并通过1H和13C NMR、ESI-MS、元素分析和熔点测试对其进行了全面表征。用单晶x射线衍射测定了前驱物之一3a的分子结构。用MTT法研究了所获得的复合物对HeLa、MGC803、A549、MDA-MB-231和MCF-7等人癌细胞的细胞毒性。而配合物4d和4e的细胞毒性明显高于顺铂(阳性对照组)和配合物3a-3e。复合物4d和4e对MCF-7细胞比MCF-10a正常细胞具有一定的选择性(选择性指数分别为7.33和7.57)。谷胱甘肽s -转移酶(GSTs)活性测定表明,配合物4d和4e比乙酸(EA,表征最好的GST抑制剂)具有更高的GST抑制活性,与它们更高的细胞毒性一致。进一步的机制研究表明,4e诱导的MCF-7细胞凋亡可能与ROS的产生、线粒体膜电位的丧失和G2/M期细胞阻滞有关。此外,对MCF-7细胞异种移植小鼠模型的体内抗肿瘤作用研究表明,复合物4e显著抑制肿瘤生长,抑制效率为68.80%,高于顺铂组(59.25%)。这些结果强调了开发与GST抑制剂功能化的带正电荷的查尔酮-羟基吡啶杂化钌(II)-芳烃配合物作为抗癌药物的可能性。
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引用次数: 0
Expanding the scope of copper artificial metalloenzymes: A potential fluorinase? 扩大铜人造金属酶的范围:一种潜在的氟化酶?
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1016/j.jinorgbio.2024.112777
Isabeau Lüddecke, Amanda G. Jarvis
Biocatalysts for fluorination are rare, and thus of great interest for artificial enzyme design. Biohybrid catalysts including Cu-based DNAzymes and dinucleotide catalysts can catalyse enantioselective electrophilic fluorination of β-ketoesters. Here we report the investigation of Cu-based artificial metalloenzymes as catalysts for electrophilic fluorination reactions. A library of artificial copper proteins was prepared by bioconjugation of bidentate and tridentate nitrogen ligands to cysteine variants of the Sterol Carrier Protein 2 L (SCP-2 L) and subsequent addition of Cu(II) salts. The resulting copper proteins were screened for activity for the fluorination of β-ketoesters using Selectfluor. Under aqueous acidic conditions it was observed that the designed catalysts did not outcompete the uncatalysed background reaction. This work highlights that careful consideration of substrate reactivity and background reactions is needed when considering potential reactions for artificial metalloenzyme catalysis.
用于氟化的生物催化剂很少,因此对人工酶的设计有很大的兴趣。包括铜基DNAzymes和二核苷酸催化剂在内的生物杂化催化剂可以催化β-酮酯的对映选择性亲电氟化。本文报道了铜基人工金属酶作为亲电氟化反应催化剂的研究进展。将双齿和三齿氮配体与甾醇载体蛋白2l (scp - 2l)的半胱氨酸变体进行生物偶联,然后加入Cu(II)盐,制备了人工铜蛋白库。用Selectfluor筛选所得铜蛋白对β-酮酯的氟化活性。在酸性水条件下,所设计的催化剂并不优于未催化的背景反应。这项工作强调,在考虑人工金属酶催化的潜在反应时,需要仔细考虑底物反应性和背景反应。
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引用次数: 0
Hemin, copper and amyloid-β: A medley involved in Alzheimer's disease. An interaction that fine regulates the reactivity 血红蛋白、铜和淀粉样蛋白-β:与阿尔茨海默病有关的混合体。精细调节反应性的相互作用
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1016/j.jinorgbio.2024.112775
Chiara Bacchella , Silvia De Caro , Stefania Nicolis , Enrico Monzani , Simone Dell'Acqua
Metal ions have been shown to play a critical role in amyloid-β (Aβ) neurotoxicity and plaque formation which are key hallmarks of Alzheimer's disease. Amyloid-β peptides can bind both copper and hemin and this interaction modulates the redox chemistry of these metals. The characterization of the binding of hemin through UV–Vis spectroscopic titration with Aβ(4-16) shows a significantly higher affinity than that with Aβ(1-16). Also, the characterization of the hemin-catalyzed oxidation through different assays (peroxidase-like activity, ascorbate oxidation, HPLC-MS analysis of peptide oxidation) displays a greater reactivity in the presence of Aβ(4-16) when compared to that of Aβ(1-16). Since the Aβ(4-16) peptide sequence contains the typical amino-terminal copper and nickel binding motif (ATCUN), this leads to investigate the potential formation of ternary hemin/copper/Aβ(4-16) adducts. The evaluation of K1 and K2 (constants that regulate the formation of five-coordinated high-spin complex and of six-coordinated low-spin complex, respectively) for mixed systems indicates that the presence of copper stabilizes the 1:1 hemin-Aβ(4-16) species, partially hindering the formation of the low-spin complex. On the other hand, the formation of the ternary hemin/copper/Aβ(4-16) complex gives rise to a less efficient catalyst, resulting in a reduction of the overall oxidative reactivity. These results suggest that the reactivity of metal ions is finely modulated by the formation of complexes with amyloid peptides and this property is also regulated differently by the various in vivo relevant isoforms.
研究表明,金属离子在淀粉样蛋白-β(Aβ)的神经毒性和斑块形成中起着关键作用,而这正是阿尔茨海默病的主要特征。淀粉样蛋白-β肽能与铜和海明结合,这种相互作用会调节这些金属的氧化还原化学反应。通过紫外可见光谱滴定 Aβ(4-16)与海明的结合特性,发现海明与 Aβ(1-16)的亲和力明显高于 Aβ(4-16)。此外,通过不同的检测方法(过氧化物酶样活性、抗坏血酸氧化、肽氧化的 HPLC-MS 分析)对海明催化氧化的表征显示,与 Aβ(1-16)相比,Aβ(4-16)存在时的反应活性更高。由于 Aβ(4-16)肽序列包含典型的氨基末端铜和镍结合基团(ATCUN),这导致了对可能形成的三元海明/铜/Aβ(4-16)加合物的研究。对混合体系的 K1 和 K2(分别调节五配位高自旋复合物和六配位低自旋复合物形成的常数)进行的评估表明,铜的存在稳定了 1:1 的 hemin-Aβ(4-16)物种,部分阻碍了低自旋复合物的形成。另一方面,三元hemin/铜/Aβ(4-16) 复合物的形成会降低催化剂的效率,导致整体氧化反应性降低。这些结果表明,金属离子的反应性受到与淀粉样肽形成的复合物的微妙调节,而且这一特性也受到各种体内相关同工酶的不同调节。
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引用次数: 0
Influence of the second coordination sphere on O2 activation by a nonheme iron(II) thiolate complex 第二配位球对非血红素铁(II)硫酸盐配合物O2活化的影响。
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-17 DOI: 10.1016/j.jinorgbio.2024.112776
Sudha Yadav, Robert S. Lyons, Zoe Readi-Brown, Maxime A. Siegler, David P. Goldberg
The synthesis and characterization of a new ligand, 1-(bis(pyridin-2-ylmethyl) amino)-2-methylpropane-2-thiolate (BPAMe2S) and its nonheme iron complex, FeII(BPAMe2S)Br (1), is reported. Reaction of 1 with O2 at −20 °C generates a high-spin iron(III)-hydroxide complex, [FeIII(OH)(BPAMe2S)(Br)] (2), that was characterized by UV–vis, 57Fe Mössbauer, and electron paramagnetic resonance (EPR) spectroscopies, and electrospray ionization mass spectrometry (ESI-MS). Density functional theory (DFT) calculations were employed to support the spectroscopic assignments. In a previous report (J. Am. Chem. Soc. 2024, 146, 7915–7921), the related iron(II) complex, FeII(BNPAMe2S)Br (BNPAMe2S = (bis((6-(neopentylamino)pyridinyl) methyl)amino)-2-methylpropane-2-thiolate) was reported and shown to react with O2 at low temperature to give a rare iron(III)-superoxide intermediate, which then converts to an S‑oxygenated sulfinate as seen for the nonheme iron thiol dioxygenases. This complex includes two hydrogen bonding neopentylamino groups in the second coordination sphere. Complex 1 does not include these H-bonding groups, and its reactivity with O2 does not yield a stabilized Fe/O2 intermediate or S‑oxygenated products, although the data suggest an inner-sphere mechanism and formation of an iron‑oxygen species that is capable of abstracting hydrogen atoms from solvent or weak CH bond substrates. This study indicates that the H-bond donors are critical for stabilizing the FeIII(O2-•) intermediate with the BNPAMe2S ligand, which in turn leads to S‑oxygenation, as opposed to H-atom abstraction, following O2 activation by the nonheme iron center.
报道了新配体1-(双(吡啶-2-甲基)氨基)-2-甲基丙烷-2-硫代酸酯(BPAMe2S-)及其非血红素铁配合物FeII(BPAMe2S)Br(1)的合成和表征。1与O2在-20℃下反应生成高自旋铁(III)-氢氧化物配合物[FeIII(OH)(BPAMe2S)(Br)](2),通过UV-vis、57Fe Mössbauer、电子顺磁共振(EPR)谱和电喷雾质谱(ESI-MS)对其进行了表征。采用密度泛函理论(DFT)计算支持光谱分配。在之前的一份报告中(j.a m。化学。与之相关的铁(II)配合物FeII(BNPAMe2S)Br (BNPAMe2S- = (bis((6-(neopentylamino)pyridinyl) methyl)amino)-2-methylpropane-2-thiolate)在低温下与O2反应生成稀有的铁(III)-超氧化物中间体,然后转化为S-氧合亚硫酸盐,如非血红素铁硫醇双加氧酶所见。该配合物在第二配位球中包含两个氢键新戊基氨基。配合物1不包括这些氢键基团,它与O2的反应性不会产生稳定的Fe/O2中间产物或S氧产物,尽管数据表明球内机制和铁氧物质的形成能够从溶剂或弱CH键底物中提取氢原子。该研究表明,氢键供体对于用BNPAMe2S-配体稳定FeIII(O2-•)中间体至关重要,这反过来导致非血红素铁中心O2活化后的S-氧合,而不是h原子的提取。
{"title":"Influence of the second coordination sphere on O2 activation by a nonheme iron(II) thiolate complex","authors":"Sudha Yadav,&nbsp;Robert S. Lyons,&nbsp;Zoe Readi-Brown,&nbsp;Maxime A. Siegler,&nbsp;David P. Goldberg","doi":"10.1016/j.jinorgbio.2024.112776","DOIUrl":"10.1016/j.jinorgbio.2024.112776","url":null,"abstract":"<div><div>The synthesis and characterization of a new ligand, 1-(bis(pyridin-2-ylmethyl) amino)-2-methylpropane-2-thiolate (BPA<sup>Me2</sup>S<sup>−</sup>) and its nonheme iron complex, Fe<sup>II</sup>(BPA<sup>Me2</sup>S)Br (<strong>1</strong>), is reported. Reaction of <strong>1</strong> with O<sub>2</sub> at −20 °C generates a high-spin iron(III)-hydroxide complex, [Fe<sup>III</sup>(OH)(BPA<sup>Me2</sup>S)(Br)] (<strong>2</strong>), that was characterized by UV–vis, <sup>57</sup>Fe Mössbauer, and electron paramagnetic resonance (EPR) spectroscopies, and electrospray ionization mass spectrometry (ESI-MS). Density functional theory (DFT) calculations were employed to support the spectroscopic assignments. In a previous report (<em>J. Am. Chem. Soc.</em> <strong>2024</strong>, <em>146</em>, 7915–7921), the related iron(II) complex, Fe<sup>II</sup>(BNPA<sup>Me2</sup>S)Br (BNPA<sup>Me2</sup>S<sup>−</sup> = (bis((6-(neopentylamino)pyridinyl) methyl)amino)-2-methylpropane-2-thiolate) was reported and shown to react with O<sub>2</sub> at low temperature to give a rare iron(III)-superoxide intermediate, which then converts to an S‑oxygenated sulfinate as seen for the nonheme iron thiol dioxygenases. This complex includes two hydrogen bonding neopentylamino groups in the second coordination sphere. Complex <strong>1</strong> does not include these H-bonding groups, and its reactivity with O<sub>2</sub> does not yield a stabilized Fe/O<sub>2</sub> intermediate or S‑oxygenated products, although the data suggest an inner-sphere mechanism and formation of an iron‑oxygen species that is capable of abstracting hydrogen atoms from solvent or weak C<img>H bond substrates. This study indicates that the H-bond donors are critical for stabilizing the Fe<sup>III</sup>(O<sub>2</sub><sup>-•</sup>) intermediate with the BNPA<sup>Me2</sup>S<sup>−</sup> ligand, which in turn leads to S‑oxygenation, as opposed to H-atom abstraction, following O<sub>2</sub> activation by the nonheme iron center<sub>.</sub></div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112776"},"PeriodicalIF":3.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Physiological iron chelators pyrophosphate and citrate have different effects on the proportions of monoferric transferrin metalloforms 生理铁螯合剂焦磷酸盐和柠檬酸盐对单铁转铁蛋白金属形态比例的影响不同
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-17 DOI: 10.1016/j.jinorgbio.2024.112773
Shelby T. Harris, Jordan Gardner, Alexia Davis, Julia Steed, Steven Christiansen, Stewart Ryberg, Weston Ludlow, Mitchell Pendleton, Blake Grimshaw, Richard K. Watt
Human serum transferrin can bind up to two iron atoms, one in each of its two domains which are known as the N-lobe and the C-lobe. Ferric pyrophosphate and ferric citrate have been shown to direct loading into the C-lobe and N-lobe, respectively. We report that the iron supplement ferric pyrophosphate citrate directs iron to the C-lobe. We also show that pyrophosphate directs iron to the C-lobe as a free anion even at the concentrations found in human plasma. This indicates that pyrophosphate may play a physiological role in transferrin iron loading and body iron homeostasis. We also present a validation of an existing micellar capillary electrophoresis technique for separating the four transferrin metalloforms, which has potential to be adapted for use in a clinical setting.
人血清转铁蛋白最多可结合两个铁原子,在其两个结构域(即 N-叶和 C-叶)中各有一个。焦磷酸铁和柠檬酸铁已被证明可分别引导转铁蛋白进入 C-叶和 N-叶。我们报告说,铁补充剂焦磷酸铁柠檬酸盐能引导铁进入 C-叶。我们还发现,即使在人体血浆中发现的浓度下,焦磷酸铁也能以游离阴离子的形式将铁导向 C-叶。这表明焦磷酸盐可能在转铁蛋白铁负荷和体内铁平衡中发挥生理作用。我们还对现有的胶束毛细管电泳技术进行了验证,以分离四种转铁蛋白金属形态,该技术有望应用于临床。
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引用次数: 0
Myxinidin-analogs able to sequester Fe(III): Metal-based gun to combat Pseudomonas aeruginosa biofilm Myxinidin-analogs 能够螯合 Fe(III):对抗铜绿假单胞菌生物膜的金属枪。
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-15 DOI: 10.1016/j.jinorgbio.2024.112774
Rosa Bellavita , Bruno Casciaro , Valeria Nocerino , Sara Palladino , Maria Rosa Loffredo , Principia Dardano , Luca De Stefano , Lucia Falcigno , Gabriella D'Auria , Stefania Galdiero , Annarita Falanga
Bacteria have developed a tendency to form biofilms, where bacteria live in organized structures embedded in a self-produced matrix of DNA, proteins, and polysaccharides. Additionally, bacteria need iron(III) as an essential nutrient for bacterial growth and secrete siderophore groups that sequester it from the environment. To design a molecule able both to inhibit the bacteria and to sequester iron, we developed two hydroxamate-based peptides derived from an analog (WMR-4), previously developed in our lab, of the antimicrobial peptide myxinidin.
In detail, we proposed a combination of WMR-4 with the hydroxamic acid resulting in the peptides WMR-7 and WMR-16 which differ for the length of the linker between the antimicrobial moiety and the siderophore. Both peptides were characterized through a set of different biophysical experiments to investigate their ability to sequester Fe3+. The peptide‑iron(III) complexes were studied through the UV–visible spectroscopy in organic solvent to eliminate water competition, and in acidic water to avoid iron precipitation. The complexes were also characterized by performing electrochemistry, circular dichroism and NMR spectroscopy experiments. In addition, we demonstrated the ability of peptide‑iron(III) complexes to inhibit the biofilm of Pseudomonas aeruginosa and to have an impact on the cell motility. This metal-based approach consisting in a hydroxamic acid conjugation represents a promising strategy to enhance the antibiofilm activity of antimicrobial peptides against one of most dangerous bacteria such as Pseudomonas aeruginosa.
细菌有形成生物膜的趋势,在生物膜中,细菌生活在有组织的结构中,嵌入由 DNA、蛋白质和多糖组成的自生基质中。此外,细菌生长需要铁(III)作为必要的营养物质,并分泌嗜铁基团从环境中截留铁(III)。为了设计一种既能抑制细菌又能封存铁的分子,我们开发了两种基于羟基氨基甲酸酯的肽,它们来自我们实验室以前开发的抗菌肽 myxinidin 的类似物(WMR-4)。具体来说,我们建议将 WMR-4 与羟肟酸结合,从而产生 WMR-7 和 WMR-16 肽,这两种肽在抗菌分子和苷元之间的连接体长度上有所不同。通过一系列不同的生物物理实验对这两种肽进行了表征,以研究它们封存 Fe3+ 的能力。肽-铁(III)复合物在有机溶剂中通过紫外-可见光谱进行研究,以消除水的竞争,在酸性水中则通过紫外-可见光谱进行研究,以避免铁沉淀。我们还通过电化学、圆二色光谱和核磁共振光谱实验对复合物进行了表征。此外,我们还证明了肽铁(III)复合物抑制铜绿假单胞菌生物膜和影响细胞运动的能力。这种基于羟肟酸共轭的金属方法是一种很有前途的策略,能增强抗菌肽对铜绿假单胞菌等最危险细菌的抗生物膜活性。
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引用次数: 0
Targeting bacterial efflux pump effectively enhances the efficacy of Ru-based antibacterial agents against Gram-negative pathogen 以细菌外排泵为靶点可有效提高 Ru 类抗菌剂对革兰氏阴性病原体的疗效。
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-06 DOI: 10.1016/j.jinorgbio.2024.112772
Yun Song , Jing Wang , Yajun Sun , Shijia Dong , Guangying Yu , Wenjing Lin , Yinhua Xiong , Yanhui Tan , Yanshi Xiong , Guijuan Jiang , Jintao Wang , Xiangwen Liao , Lianghong Liu
The rise of antibiotic resistance has posed a great threat to human's life, thus develop novel antibacterial agents is urgently needed. It worthies to noted that Ru-based antibacterial agents often showed robust potency against Gram-positive pathogens, disrupted bacterial membrane and avoided bacterial resistance, making they promising antibiotic candidates. However, they are generally less active when applied to negative pathogens. To address this problem, a Ru-based metalloantibiotic (RuN) modified with a nitrothiophene moiety, which can target bacterial efflux pump, was designed and evaluated in this work. A series of assays demonstrated that RuN not only fully retained the advantages of Ru-based agents, such as destroyed bacterial membrane and induced reactive oxygen species production, but also can targeted bacterial efflux pumps. Of course, these properties make it effective in killing both Gram-positive and negative pathogens, its MIC values against Staphylococcus aureus and Escherichia coli lies at 3.125 and 6.25 μg/mL, respectively. Importantly, RuN also showed low toxicity and has robust anti-infective potency in two animal infection models. Together, our results paved an alternative way to enhance the anti-infective efficacy of Ru-based agents against resistant negative bacteria.
抗生素耐药性的增加对人类生命构成了巨大威胁,因此开发新型抗菌剂迫在眉睫。值得注意的是,基于 Ru 的抗菌剂通常对革兰氏阳性病原体表现出强大的效力,能破坏细菌膜并避免细菌产生抗药性,因此是很有前途的抗生素候选物。然而,当它们用于阴性病原体时,活性通常较低。为解决这一问题,本研究设计并评估了一种由硝基噻吩分子修饰的 Ru 基金属抗生素(RuN),它可以靶向细菌外排泵。一系列检测结果表明,RuN 不仅完全保留了 Ru 类药物的优点,如破坏细菌膜和诱导活性氧产生,而且还能靶向细菌外排泵。当然,这些特性使其能有效杀死革兰氏阳性和阴性病原体,其对金黄色葡萄球菌和大肠杆菌的 MIC 值分别为 3.125 和 6.25 μg/mL。重要的是,RuN 在两种动物感染模型中也显示出低毒性和强大的抗感染效力。总之,我们的研究结果为提高基于 Ru 的制剂对耐药阴性细菌的抗感染效力铺平了道路。
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引用次数: 0
Multifunctional Ru(III)/Fe3O4/DNA nanoplatform for photothermal-enhanced photodynamic and chemodynamic cancer therapy 用于光热增强型光动力和化学动力癌症疗法的多功能 Ru(III)/Fe3O4/DNA 纳米平台
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-02 DOI: 10.1016/j.jinorgbio.2024.112771
Jinfeng Zheng , Xiufeng Wang , Huan Du , Ruyan Zhang , Xiaobing Huo , Ting Zhou , Guodong Zhang , Fang Wang , Qianxiong Zhou , Zhiqing Zhang
Among the many cancer treatment methods, there have been many reports on the use of nanoplatforms with single treatment methods such as photothermal, photodynamic or chemodynamic for cancer treatment. In this study, Ru(III) with photodynamic effect and Fe3O4 nanoparticles with photothermal and chemodynamic effects are connected through long DNA chains with efficient active targeting rolling circle amplification to construct Ru(III)/Fe3O4/DNA nano-platform realizes the combination of photothermal, photodynamic and chemodynamic treatment, which significantly improves the therapeutic effect of the nano-platform. Its multiple active targeting capabilities reduce the damage to normal cells. Ru(III) has excellent photodynamic effect and can catalyze the respiration product NADH (Nicotinamide adenine dinucleotide)to produce highly oxidizing H2O2. Fe3O4 NPs has weak absorption at 808 nm indicates that it can perform mild photothermal treatment, and the Fe2+ in it can react with H2O2 to produce ·OH and participate in chemodynamic treatment. Each repeating unit on the rolling circle amplified DNA long chain is connected to the AS1411 aptamer that can actively target cancer cells. Unlike the passive targeting of other nanomedicines, active and efficient targeting is achieved, and a small amount of drugs can achieve high efficacy. The therapeutic effect also reduces the damage to normal cells. The comprehensive killing effect of Ru(III)/Fe3O4/DNA can reach 85.1 %. Its high targeting of cancer cells can also be used for imaging detection of cancer cells. This new nanoplatform provides an idea for the synergy of multiple cancer treatments.
在众多癌症治疗方法中,利用光热、光动力或化学动力等单一治疗方法的纳米平台治疗癌症的报道很多。本研究将具有光动力效应的Ru(III)和具有光热和化学动力效应的Fe3O4纳米粒子通过具有高效主动靶向滚圆放大作用的长DNA链连接起来,构建了Ru(III)/Fe3O4/DNA纳米平台,实现了光热、光动力和化学动力治疗的结合,显著提高了纳米平台的治疗效果。其多重活性靶向能力可减少对正常细胞的损伤。Ru(III)具有良好的光动力效应,能催化呼吸产物 NADH(烟酰胺腺嘌呤二核苷酸)产生高氧化性 H2O2。Fe3O4 NPs 在 808 纳米波长处有微弱的吸收,表明它可以进行温和的光热治疗,其中的 Fe2+ 可以与 H2O2 反应生成-OH,参与化学动力学治疗。滚圆扩增 DNA 长链上的每个重复单元都与 AS1411 合体相连,可以主动靶向癌细胞。与其他纳米药物的被动靶向不同,它实现了主动高效靶向,少量药物就能达到很高的疗效。治疗效果还能减少对正常细胞的损伤。Ru(III)/Fe3O4/DNA 的综合杀伤效果可达 85.1%。它对癌细胞的高度靶向性还可用于癌细胞的成像检测。这种新型纳米平台为多种癌症治疗方法的协同作用提供了一种思路。
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引用次数: 0
Exploring divalent metal ion coordination. Unraveling binding modes in Staphylococcus aureus MntH fragments 探索二价金属离子的配位。揭示金黄色葡萄球菌 MntH 片段的结合模式。
IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1016/j.jinorgbio.2024.112769
Valentyn Dzyhovskyi , Maurizio Remelli , Kamila Stokowa-Sołtys
Metal ion coordination is crucial in bacterial metabolism, while divalent metal ions serve as essential cofactors for various enzymes involved in cellular processes. Therefore, bacteria have developed sophisticated regulatory mechanisms to maintain metal homeostasis. These involve protein interactions for metal ion uptake, efflux, intracellular transport, and storage. Staphylococcus aureus, a member of the commensal flora, colonizes the anterior nares and skin harmlessly but can cause severe illness. MntH transporter is responsible for acquiring divalent metal ions necessary for metabolic functions and virulence. It is a 450-amino-acid protein analogous to Nramp1 (Natural Resistance-Associated Macrophage Protein 1) in mammals. Herein, the coordination modes of copper(II), iron(II), and zinc(II) ions with select fragments of the MntH were established employing potentiometry, mass spectrometry, and spectroscopic methods. Four model peptides, MNNKRHSTNE–NH2, Ac-KFDHRSS–NH2, Ac-IMPHNLYLHSSI–NH2, and Ac-YSRHNNEE–NH2, were chosen for their metal-binding capabilities and examined to determine their coordination properties and preferences. Our findings suggest that under physiological pH conditions, the N-terminal fragment of MntH demonstrates the highest thermodynamic stability with copper(II) and iron(II) ions. Furthermore, a comparison with other peptides from the S. aureus FeoB transporter indicates different binding affinities.
金属离子配位在细菌的新陈代谢中至关重要,而二价金属离子则是参与细胞过程的各种酶所必需的辅助因子。因此,细菌开发了复杂的调节机制来维持金属平衡。这些机制涉及金属离子摄取、外流、细胞内运输和储存的蛋白质相互作用。金黄色葡萄球菌是共生菌群中的一员,定植于前鼻孔和皮肤,对人体无害,但可导致严重疾病。MntH 转运体负责获取代谢功能和毒力所需的二价金属离子。它是一种含有 450 个氨基酸的蛋白质,类似于哺乳动物中的 Nramp1(自然抗性相关巨噬细胞蛋白 1)。本文采用电位测定法、质谱法和光谱法确定了铜(II)、铁(II)和锌(II)离子与 MntH 某些片段的配位模式。我们选择了四种具有金属结合能力的模型肽:MNNKRHSTNE-NH2、Ac-KFDHRSS-NH2、Ac-IMPHNLYLHSSI-NH2 和 Ac-YSRHNEE-NH2,并对它们进行了研究,以确定它们的配位特性和偏好。我们的研究结果表明,在生理 pH 值条件下,MntH 的 N 端片段与铜(II)和铁(II)离子的热力学稳定性最高。此外,与来自金黄色葡萄球菌 FeoB 转运体的其他肽的比较表明,它们具有不同的结合亲和力。
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引用次数: 0
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Journal of Inorganic Biochemistry
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