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Gadolinium(III) complex formation with a β-cyclodextrin ligand: an XAS study of a potential MRI contrast agent 钆(III)配合物与β-环糊精配体的形成:一种潜在MRI造影剂的XAS研究。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-11-20 DOI: 10.1007/s00775-023-02027-9
Farideh Jalilehvand, Saba Homayonia, Ping Zhang, Chang-Chun Ling

In the search for improved and safer gadolinium-based magnetic resonance imaging (MRI) contrast agents, macrocyclic cyclodextrins (CDs) attract great interest. Our group previously synthesized a cyclodextrin-based ligand with 1,2,3-triazolmethyl residues conjugated to β-CD, called β-CD(A), which efficiently chelates Gd(III) ions. To probe the local structure around the Gd(III) ion in the 1:1 Gd(III): β-CD(A) complex in aqueous solution (pH 5.5), we used extended X-ray absorption fine structure (EXAFS) spectroscopy. Least-squares curve fitting of the Gd L3-edge EXAFS spectrum revealed 5 Gd–O (4 COO and 1 H2O) and 4 Gd–N (from two imino and two 1,2,3-triazole groups) bonds around the Gd(III) ion with average distances 2.36 and 2.56 ± 0.02 Å, respectively. A similar EXAFS spectrum was obtained from an aqueous solution of the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)], also 9-coordinated in its first shell. Careful analysis revealed that the mean Gd–N distance is shorter in the Gd(III): β-CD(A) (1:1) complex, indicating stronger Gd–N bonding and stronger Gd(III) complex formation than with the DOTA4− ligand. This is consistent with the lower free Gd3+ concentration found previously for the Gd(III): β-CD(A) (1:1) complex than for the [Gd(DOTA)(H2O)] complex, and shows its potential as an MRI probe.

Graphical abstract

EXAFS spectroscopy revealed a similar Gd(III) 9-coordination although slightly stronger for a modified β-cyclodextrin: Gd(III) 1:1 complex, [Gd(LH4)]7−, in aqueous solution than for the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)].

在寻找改进和安全的钆基磁共振成像(MRI)造影剂的过程中,大环环糊精(cd)引起了人们的极大兴趣。本课课组先前合成了一种以环糊精为基础的配体,其1,2,3-三唑甲基残基与β-CD偶联,称为β-CD(a),可有效地螯合Gd(III)离子。为了探测pH 5.5水溶液中1:1 Gd(III): β-CD(A)配合物中Gd(III)离子周围的局部结构,我们采用扩展x射线吸收精细结构(EXAFS)光谱法。Gd(III)离子的最小二乘曲线拟合显示Gd(III)离子周围有5个Gd- o(4个COO-和1个H2O)和4个Gd- n(来自两个亚硝基和两个1,2,3-三唑基)键,平均距离分别为2.36和2.56±0.02 Å。从临床使用的MRI造影剂Na[Gd(DOTA)(H2O)]的水溶液中获得了类似的EXAFS光谱,其第一壳层也是9配位的。仔细分析发现,Gd(III): β-CD(A)(1:1)配合物中Gd- n的平均距离较短,表明与DOTA4-配体相比,Gd- n成键更强,Gd(III)配合物形成更强。这与先前发现的Gd(III): β-CD(A)(1:1)复合物比[Gd(DOTA)(H2O)]-复合物的游离Gd3+浓度低一致,并显示其作为MRI探针的潜力。EXAFS光谱显示了类似的Gd(III) 9配位,尽管修饰的β-环糊精:Gd(III) 1:1配合物[Gd(LH4)]7-在水溶液中比临床使用的MRI造影剂Na[Gd(DOTA)(H2O)]稍强。
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引用次数: 0
Multistep synthesis of a novel copper complex with potential for Alzheimer’s disease diagnosis 一种具有阿尔茨海默病诊断潜力的新型铜配合物的多步合成。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-11-17 DOI: 10.1007/s00775-023-02028-8
Fatma Dellal, Diego Santo Domingo Porqueras, Stacy Narayanin-Richenapin, Marine Thimotee, Vanessa Delahaye, Yacine Diouf, Karolina Piasta, Elżbieta Gumienna-Kontecka, Henryk Kozlowski, Maryline Beyler, Raphael Tripier, Alban Moyeux, Olivier Gager, Valérie Besnard, Milena Salerno

Positron emission tomography (PET) imaging of Aβ plaques, is recognized as a tool for the diagnosis of Alzheimer’s disease. As a contribution to the development of new strategies for early diagnosis of the disease, using PET medical imaging technique, a new copper complex, the [Cu(TE1PA-ONO)]+ was synthesized in ten steps. The key step of our strategy is the coupling of a monopicolinate-N-alkylated cyclam-based ligand with a moiety capable of recognizing Aβ plaques via a successful and challenging Buchwald-Hartwig coupling reaction. To our knowledge, it is the first time that such a strategy is used to functionalize polyazamacrocyclic derivatives. The thermodynamic stability constants determined in MeOH/H2O solvent indicate that the attachment of this moiety does not weaken the chelating properties of TE1PA-ONO ligand in relation to parent HTE1PA. The novel complex described here is able to recognize amyloid plaques in brain sections from Alzheimer's disease patients and shows low toxicity to human neuronal cells.

Graphical abstract

正电子发射断层扫描(PET)成像的a β斑块,是公认的一种工具,用于诊断阿尔茨海默病。利用PET医学成像技术,分十步合成了一种新的铜配合物[Cu(TE1PA-ONO)]+,为疾病早期诊断的新策略的发展做出贡献。我们策略的关键步骤是通过一个成功且具有挑战性的Buchwald-Hartwig偶联反应,将单古碱- n -烷基化环聚糖基配体与能够识别β斑块的片段偶联。据我们所知,这是第一次使用这种策略来功能化多氮杂环衍生物。在MeOH/H2O溶剂中测定的热力学稳定性常数表明,该部分的附着不会削弱TE1PA-ONO配体相对于母体HTE1PA的螯合性能。这里描述的新型复合物能够识别阿尔茨海默病患者脑切片中的淀粉样斑块,并显示对人类神经元细胞的低毒性。
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引用次数: 0
In vitro and in vivo accumulation of the anticancer Ru complexes [RuII(cym)(HQ)Cl] and [RuII(cym)(PCA)Cl]Cl 抗癌络合物[RuII(cym)(HQ)Cl]和[RuII(cym)(PCA)Cl]Cl的体外和体内积累。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-11-14 DOI: 10.1007/s00775-023-02026-w
Mie Riisom, Stuart J. Morrow, Caitlin D. Herbert, William D. J. Tremlett, Jonathan W. Astin, Stephen M. F. Jamieson, Christian G. Hartinger

The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes [RuII(cym)(HQ)Cl] 1 (cym = η6-p-cymene, HQ = 8-hydroxyquinoline) and [RuII(cym)(PCA)Cl]Cl 2 (PCA = N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl2 resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.

Graphical abstract

研究了两种钌基抗癌复合物[RuII(cym)(HQ)Cl] 1 (cym = φ 6-p-cymene, HQ = 8-羟基喹啉)和[RuII(cym)(PCA)Cl]Cl 2 (PCA = n -氟苯基-2-吡啶碳硫酰胺)在HCT116人结直肠癌细胞中的积累及其机制。结果表明,这两种复合物的细胞积累随着时间和浓度的增加而增加,其中2在细胞中的积累量大于1。选择性细胞积累机制的抑制研究表明,1和2可能通过被动扩散和主动转运体转运到细胞中,类似于顺铂。外排实验表明1和2通过不涉及p糖蛋白的机制进行外排,因为维拉帕米的添加没有任何影响。通过添加CuCl2来探索Cu转运体的影响导致1和2的积累增加,而顺铂处理细胞时检测到的Pt量略有减少。利用ICP-MS和LA-ICP-MS测定了配合物1和2在斑马鱼体内的积累和分布。结果与体外观察结果相关,2处理的斑马鱼Ru含量高于1处理的斑马鱼。分布研究表明,这两种复合物主要积聚在斑马鱼的肠道中。
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引用次数: 0
Dinuclear gold(I) complexes based on carbene and diphosphane ligands: bis[2-(dicyclohexylphosphano)ethyl]amine complex inhibits the proteasome activity, decreases stem cell markers and spheroid viability in lung cancer cells 基于碳烯和二膦配体的双核金(I)配合物:双[2-(双环己基磷酸)乙基]胺配合物抑制蛋白酶体活性,降低肺癌细胞干细胞标记物和球体活力。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-11-13 DOI: 10.1007/s00775-023-02025-x
Naike Casagrande, Cinzia Borghese, Giuseppe Corona, Donatella Aldinucci, Muhammad Altaf, Adam A. A. Sulaiman, Anvarhusein A. Isab, Saeed Ahmad, Abdul Malik P. Peedikakkal

Three new dinuclear gold(I) complexes (13) containing a carbene (1,3-Bis(2,6-di-isopropylphenyl)imidazol-2-ylidene (IPr)) and diphosphane ligands [bis(1,2-diphenylphosphano)ethane (Dppe), bis(1,3-diphenylphosphano)propane (Dppp) and bis[2-(dicyclohexylphosphano)ethyl]amine (DCyPA)], were synthesized and characterized by elemental analysis and, ESI–MS, mid FT-IR and NMR spectroscopic methods. The structures of complexes 2 and 3 were determined by X-ray crystallography, which revealed that the complexes are dinuclear having gold(I) ions linearly coordinated. The anticancer activities of the complexes (1–3) were evaluated in lung (A549), breast (MC-F7), prostate (PC-3), osteosarcoma (MG-63) and ovarian (A2780 and A2780cis) cancer models. Growth inhibition by the new complexes was higher than cisplatin in all cell lines tested. The mechanism of action of complex 3 was investigated in A549 cells using 2-dimensional (2D) models and 3D-multicellular tumor spheroids. Treatment of A549 cells with complex 3 caused: the induction of apoptosis and the generation of reactive oxygen species; the cell cycle arrest in the G0/G1 phase; the inhibition of both the proteasome and the NF-kB activity; the down-regulation of lung cancer stem cell markers (NOTCH1, CD133, ALDH1 and CD44). Complex 3 was more active than cisplatin also in 3D models of A549 lung cancer cells.

Grahical abstract

合成了三种新的双核金(I)配合物(1-3),其中含有1,3-二(2,6-二异丙基苯基)咪唑-2-酰基(IPr))和二膦配体[2(1,2-二苯基磷)乙烷(Dppe), 2(1,3-二苯基磷)丙烷(Dppp)和2-(双环己基磷)乙基]胺(DCyPA)],并通过元素分析、ESI-MS、mid - FT-IR和NMR等方法对其进行了表征。通过x射线晶体学对配合物2和3的结构进行了分析,结果表明配合物为双核结构,金离子线性配位。在肺癌(A549)、乳腺癌(MC-F7)、前列腺癌(PC-3)、骨肉瘤(MG-63)和卵巢癌(A2780和A2780cis)模型中评价复合物(1-3)的抗癌活性。新复合物对所有细胞系的生长抑制作用均高于顺铂。利用二维(2D)模型和三维多细胞肿瘤球体研究复合物3在A549细胞中的作用机制。复合物3对A549细胞的处理引起:诱导细胞凋亡和活性氧的产生;细胞周期停留在G0/G1期;蛋白酶体和NF-kB活性均受到抑制;肺癌干细胞标志物(NOTCH1、CD133、ALDH1和CD44)的下调。复合物3在A549肺癌细胞的3D模型中也比顺铂更有活性。
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引用次数: 0
Circular permutation at azurin’s active site slows down its folding azurin活性位点的环状排列减慢了它的折叠速度。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-11-13 DOI: 10.1007/s00775-023-02023-z
Debanjana Das, Sri Rama Koti Ainavarapu

Circular permutation (CP) is a technique by which the primary sequence of a protein is rearranged to create new termini. The connectivity of the protein is altered but the overall protein structure generally remains unperturbed. Understanding the effect of CP can help design robust proteins for numerous applications such as in genetic engineering, optoelectronics, and improving catalytic activity. Studies on different protein topologies showed that CP usually affects protein stability as well as unfolding rates. Though a significant number of proteins contain metals or other cofactors, reports of metalloprotein CPs are rare. Thus, we chose a bacterial metalloprotein, azurin, and its CP within the metal-binding site (cpF114). We studied the stabilities, folding, and unfolding rates of apo- and Zn2+-bound CP azurin using fluorescence and circular dichroism. The introduced CP had destabilizing effects on the protein. Also, the folding of the Zn2+-CP protein was much slower than that of the Zn2+-WT or apo-protein. We compared this study to our previously reported azurin-cpN42, where we had observed an equilibrium and kinetic intermediate. cpF114 exhibits an apparent two-state equilibrium unfolding but has an off-pathway kinetic intermediate. Our study hinted at CP as a method to modify the energy landscape of proteins to alter their folding pathways. WT azurin, being a faster folder, may have evolved to optimize the folding rate of metal-bound protein compared to its CPs, albeit all of them have the same structure and function. Our study underscores that protein sequence and protein termini positions are crucial for metalloproteins.

Graphical abstract

TOC Figure. (Top) Zn2+-azurin WT structure (PDB code: 1E67) and 2-D topology diagram of Zn2+-cpF114 azurin. (Bottom) Cartoon diagram representing folding (red arrows) and unfolding (blue arrows) of apo- and Zn2+- WT and cpF114 azurins. The width of the arrows represents the rate of the corresponding processes.

环状排列(CP)是一种将蛋白质的原序列重新排列以产生新末端的技术。蛋白质的连通性被改变,但蛋白质的整体结构通常保持不变。了解CP的作用可以帮助设计健壮的蛋白质,用于许多应用,如基因工程、光电子学和提高催化活性。对不同蛋白质拓扑结构的研究表明,CP通常会影响蛋白质的稳定性和展开速率。虽然大量蛋白质含有金属或其他辅助因子,但关于金属蛋白CPs的报道很少。因此,我们选择了一种细菌金属蛋白azurin及其金属结合位点内的CP (cpF114)。我们利用荧光和圆二色性研究了apo-和Zn2+结合的CP azurin的稳定性、折叠和展开率。引入的CP对蛋白质具有不稳定作用。此外,Zn2+-CP蛋白的折叠速度也比Zn2+-WT或载脂蛋白慢得多。我们将这项研究与我们之前报道的azurin-cpN42进行了比较,在那里我们观察到一个平衡和动力学中间产物。cpF114表现出明显的两态平衡展开,但有一个非通路的动力学中间体。我们的研究暗示CP是一种改变蛋白质能量格局以改变其折叠途径的方法。WT azurin作为一种更快的折叠器,可能已经进化到优化金属结合蛋白的折叠速率,尽管它们都具有相同的结构和功能。我们的研究强调了蛋白质序列和蛋白质末端位置对金属蛋白至关重要。TOC的人物。(上)Zn2+-azurin WT结构(PDB代码:1E67)和Zn2+-cpF114 azurin的二维拓扑图。(下)apo-、Zn2+- WT和cpF114 azurins的折叠(红色箭头)和展开(蓝色箭头)的卡通图。箭头的宽度表示相应过程的速率。
{"title":"Circular permutation at azurin’s active site slows down its folding","authors":"Debanjana Das,&nbsp;Sri Rama Koti Ainavarapu","doi":"10.1007/s00775-023-02023-z","DOIUrl":"10.1007/s00775-023-02023-z","url":null,"abstract":"<div><p>Circular permutation (CP) is a technique by which the primary sequence of a protein is rearranged to create new termini. The connectivity of the protein is altered but the overall protein structure generally remains unperturbed. Understanding the effect of CP can help design robust proteins for numerous applications such as in genetic engineering, optoelectronics, and improving catalytic activity. Studies on different protein topologies showed that CP usually affects protein stability as well as unfolding rates. Though a significant number of proteins contain metals or other cofactors, reports of metalloprotein CPs are rare. Thus, we chose a bacterial metalloprotein, azurin, and its CP within the metal-binding site (cpF114). We studied the stabilities, folding, and unfolding rates of apo- and Zn<sup>2+</sup>-bound CP azurin using fluorescence and circular dichroism. The introduced CP had destabilizing effects on the protein. Also, the folding of the Zn<sup>2+</sup>-CP protein was much slower than that of the Zn<sup>2+</sup>-WT or apo-protein. We compared this study to our previously reported azurin-cpN42, where we had observed an equilibrium and kinetic intermediate. cpF114 exhibits an apparent two-state equilibrium unfolding but has an off-pathway kinetic intermediate. Our study hinted at CP as a method to modify the energy landscape of proteins to alter their folding pathways. WT azurin, being a faster folder, may have evolved to optimize the folding rate of metal-bound protein compared to its CPs, albeit all of them have the same structure and function. Our study underscores that protein sequence and protein termini positions are crucial for metalloproteins. </p><h3>Graphical abstract</h3><p>TOC Figure. (Top) Zn<sup>2+</sup>-azurin WT structure (PDB code: 1E67) and 2-D topology diagram of Zn<sup>2+</sup>-cpF114 azurin. (Bottom) Cartoon diagram representing folding (red arrows) and unfolding (blue arrows) of apo- and Zn<sup>2+</sup>- WT and cpF114 azurins. The width of the arrows represents the rate of the corresponding processes.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":"28 8","pages":"737 - 749"},"PeriodicalIF":3.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92152177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Synthesis, antimicrobial activity and molecular docking study of benzyl functionalized benzimidazole silver(I) complexes 苄基官能化苯并咪唑-银(I)配合物的合成、抗菌活性及分子对接研究。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-11-07 DOI: 10.1007/s00775-023-02024-y
Erkan Arı, Neslihan Şahin, Elvan Üstün, Muhammed Dündar, Hüseyin Karcı, İlknur Özdemir, Ahmet Koç, Nevin Gürbüz, İsmail Özdemir

In this study, a series of N-functionalized benzimidazole silver(I) complexes were prepared and characterized by FT-IR, 1H, 13C{1H} NMR spectroscopy, and elemental analysis. Synthesized N-benzylbenzimidazole silver(I) complexes were evaluated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. The results indicated that N-alkylbenzimidazole silver(I) complexes exhibited good antimicrobial activity compared to N-alkylbenzimidazole derivatives. Especially, complex 2e presented perfect antimicrobial activity than the other complexes. The characterized molecules were optimized by DFT-based calculation methods and the optimized molecules were analyzed in detail by molecular docking methods against bacterial DNA-gyrase and CYP51. The amino acid residues detected for both target molecules are consistent with expectations, and the calculated binding affinities and inhibition constants are promising for further studies.

Graphical abstract

A series of N-alkylbenzimidazole silver(I) complexes were synthesized and fully characterized by means of 1H NMR, 13C NMR, and FT-IR spectroscopies. Synthesized N-alkylbenzimidazole silver(I) complexes were investigated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. All complexes showed better activity according to Ampicilin against Pseudomonas aeruginosa. The molecules which were firstly optimized by DFT-based calculation methods were also analyzed by molecular docking methods against DNA gyrase of E. Coli and CYP51. 338 × 190 mm (96 × 96 DPI)

在本研究中,制备了一系列N-官能化苯并咪唑-银(I)配合物,并通过FT-IR、1H、13C{1H}NMR光谱和元素分析对其进行了表征。评价了合成的N-苄基苯并咪唑-银(I)配合物对大肠杆菌、铜绿假单胞菌、金黄色葡萄球菌以及真菌株白色念珠菌和光滑念珠菌的抗菌活性。结果表明,与N-烷基苯并咪唑衍生物相比,N-烷基苯并咪唑银(I)配合物具有良好的抗菌活性。特别是配合物2e比其它配合物具有更好的抗菌活性。通过基于DFT的计算方法对表征的分子进行优化,并通过针对细菌DNA聚合酶和CYP51的分子对接方法对优化的分子进行详细分析。两种靶分子检测到的氨基酸残基与预期一致,计算出的结合亲和力和抑制常数有望用于进一步研究。合成了一系列N-烷基苯并咪唑银(I)配合物,并用1H NMR、13C NMR和FT-IR对其进行了表征。研究了合成的N-烷基苯并咪唑银(I)配合物对大肠杆菌、铜绿假单胞菌、金黄色葡萄球菌以及真菌白色念珠菌和光滑念珠菌的抗菌活性。根据氨苄青霉素,所有复合物对铜绿假单胞菌都显示出更好的活性。利用基于DFT的计算方法对首次优化的分子进行了针对大肠杆菌DNA聚合酶和CYP51的分子对接分析。338 × 190毫米(96 × 96dpi)。
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引用次数: 0
A novel palladium complex with a coumarin-thiosemicarbazone hybrid ligand inhibits Trypanosoma cruzi release from host cells and lowers the parasitemia in vivo 一种新的含有香豆素缩氨基脲杂化配体的钯络合物抑制了克氏锥虫从宿主细胞中的释放,并降低了体内寄生虫病。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-09-28 DOI: 10.1007/s00775-023-02020-2
Santiago Rostán, Samuel Porto, Cesar L. N. Barbosa, Diego Assis, Natalia Alvarez, Fabiana Simão Machado, Graciela Mahler, Lucía Otero

In this work, two analogous coumarin-thio and semicarbazone hybrid compounds were prepared and evaluated as a potential antichagasic agents. Furthermore, palladium and platinum complexes with the thiosemicarbazone derivative as ligand (L1) were obtained in order to establish the effect of metal complexation on the antiparasitic activity. All compounds were fully characterized both in solution and in solid state including the resolution of the crystal structure of the palladium complex by X-ray diffraction methods. Unexpectedly, all experimental and theoretical characterizations in the solid state, demonstrated that the obtained palladium and platinum complexes are structurally different: [PdCl(L1)] and [PtCl2(HL1)]. All the studied compounds lower the proliferation of the amastigote form of Trypanosoma cruzi while some of them also have an effect on the trypomastigote stage. Additionally, the compounds inhibit T. cruzi release from host cells in variable extents. The Pd compound presented a remarkable profile in all the in vitro experiments, and it showed no toxicity for mammalian cells in the assayed concentrations. In this sense, in vivo experiments were performed for this compound using an acute model of Chagas disease. Results showed that the complex significantly lowered the parasite count in the mice blood with no significant toxicity.

Graphical abstract

在本工作中,制备了两种类似的香豆素-硫代和氨基脲杂化化合物,并对其作为潜在的抗癌剂进行了评价。此外,获得了以氨基硫脲衍生物为配体(L1)的钯和铂络合物,以确定金属络合对抗寄生虫活性的影响。所有化合物在溶液和固态下都得到了充分的表征,包括通过X射线衍射方法对钯络合物的晶体结构的分辨率。出乎意料的是,固态下的所有实验和理论表征都表明,获得的钯和铂络合物在结构上不同:[PdCl(L1)]和[PtCl2(HL1)]。所有研究的化合物都降低了克鲁兹锥虫无鞭毛虫形式的增殖,而其中一些化合物也对锥虫期有影响。此外,这些化合物在不同程度上抑制克氏锥虫从宿主细胞中释放。Pd化合物在所有体外实验中都表现出显著的特征,并且在所测定的浓度下对哺乳动物细胞没有毒性。从这个意义上讲,使用恰加斯病的急性模型对该化合物进行了体内实验。结果表明,该复合物显著降低了小鼠血液中的寄生虫计数,没有显著毒性。
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引用次数: 0
Assessment of 13 essential and toxic trace elements in tumor and peritumoral brain tissues from human glioblastoma 人类胶质母细胞瘤肿瘤和瘤周脑组织中13种必需和有毒微量元素的评估。
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-09-23 DOI: 10.1007/s00775-023-02021-1
Hao-Long Zeng, Binmei Jia, Qing Yang, Fengbo Zeng, Huijun Li, Chao-Xi Li, Liming Cheng

Trace elements within the brain are important for proper neurological function, but their imbalance has been rarely investigated in glioblastoma. This study enrolled a total of 14 patients with glioblastoma, and the tumor and peritumoral brain tissues were collected while undergoing surgery. The concentrations of Mg, Ca, Cr, Mn, Fe, Co, Cu, Zn, Se, As, Cd, Tl and Pb were determined using a well-evaluated ICP-MS method. The Cu- and Cd-binding proteomes were further analyzed using the anatomic transcriptional atlas from Ivy GAP. Histological evaluation was based on rubeanic acid staining and immunohistochemistry, respectively. The 13 trace element concentrations were obtained, and the highest were Ca, Mn, Fe, Zn and Cu, ranging from a few to dozens of ug/g. Correlation analysis suggested the existence of two intra-correlated clusters: essential metals (Cu–Ca–Zn–Mg) and heavy metals (Pb–As–Cd–Tl–Co–Cr–Mn). Compared to the tumor samples, significantly higher levels of Cu and Cd were observed in the peritumoral region. Further analysis of the Cu- and Cd-binding proteins from the anatomic view suggested that DBH and NOS1 were obviously increased in the leading edge than the central tumor region. Consistent with the above findings, histological evaluation of Cu and DBH further confirmed more copper and DBH expressions in the peritumoral area compared to the tumor core. Trace elements differ in tumor and peritumoral brain zone in glioblastoma, which may associate with tumor angiogenesis.

Graphical abstract

大脑中的微量元素对正常的神经功能很重要,但很少在胶质母细胞瘤中研究它们的失衡。这项研究共招募了14名胶质母细胞瘤患者,在接受手术时收集肿瘤和瘤周脑组织。Mg、Ca、Cr、Mn、Fe、Co、Cu、Zn、Se、As、Cd、Tl和Pb的浓度使用评价良好的ICP-MS方法测定。利用Ivy GAP的解剖转录图谱进一步分析了Cu和Cd结合蛋白质组。组织学评价分别基于风疹染色和免疫组织化学。获得了13种微量元素的浓度,其中Ca、Mn、Fe、Zn和Cu的浓度最高,从几微克/克到几十微克/克不等。相关性分析表明存在两个内部相关的簇:必需金属(Cu-Ca-Zn-Mg)和重金属(Pb-As-Cd-Tl-Co-Cr-Mn)。与肿瘤样本相比,在肿瘤周围区域观察到明显更高水平的Cu和Cd。从解剖学角度对Cu和Cd结合蛋白的进一步分析表明,肿瘤前缘的DBH和NOS1明显高于肿瘤中心区。与上述发现一致,Cu和DBH的组织学评估进一步证实,与肿瘤核心相比,肿瘤周围区域有更多的铜和DBH表达。胶质母细胞瘤中肿瘤和瘤周脑区的微量元素不同,这可能与肿瘤血管生成有关。
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引用次数: 0
Initial characterization of an iron superoxide dismutase from Thermobifida fusca 褐藻热裂菌铁超氧化物歧化酶的初步鉴定
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-09-19 DOI: 10.1007/s00775-023-02019-9
Anne Grethe Hamre, Rim Al-Sadawi, Kirsti Merete Johannesen, Bastien Bisarro, Åsmund Røhr Kjendseth, Hanna-Kirsti S. Leiros, Morten Sørlie

Superoxide dismutases (SODs) are enzymes that catalyze the dismutation of the superoxide radical anion into O2 and H2O2 in a two-step reaction. They are ubiquitous to all forms of life and four different types of metal centers are detected, dividing this class of enzymes into Cu-/Zn-, Ni-, Mn-, and Fe-SODs. In this study, a superoxide dismutase from the thermophilic bacteria Thermobifida fusca (TfSOD) was cloned and expressed before the recombinant enzyme was characterized. The enzyme was found to be active for superoxide dismutation measured by inhibition of cytochrome c oxidation and the inhibition of the autoxidation of pyrogallol. Its pH-optimum was determined to be 7.5, while it has a broad temperature optimum ranging from 20 to 90 °C. Combined with the Tm that was found to be 78.5 ± 0.5 °C at pH 8.0, TfSOD can be defined as a thermostable enzyme. Moreover, the crystal structure of TfSOD was determined and refined to 1.25 Å resolution. With electron paramagnetic resonance spectroscopy, it was confirmed that iron is the metal co-factor of TfSOD. The cell potential (Em) for the TfSOD-Fe3+/TfSOD-Fe2+ redox couple was determined to be 287 mV.

Graphical abstract

超氧化物歧化酶(SODs)是在两步反应中催化超氧化物自由基阴离子歧化为O2和H2O2的酶。它们普遍存在于所有形式的生命中,并检测到四种不同类型的金属中心,将这类酶分为Cu/Zn-、Ni-、Mn-和Fe-SOD。在本研究中,从嗜热细菌褐藻热裂中克隆并表达了超氧化物歧化酶(TfSOD),然后对重组酶进行了表征。通过抑制细胞色素c氧化和抑制邻苯三酚的自氧化,发现该酶对超氧化物歧化具有活性。其最适pH值为7.5,而最适温度范围为20至90°C。结合Tm发现为78.5 ± 在0.5°C、pH 8.0的条件下,TfSOD可以被定义为一种耐热酶。此外,测定了TfSOD的晶体结构,并将其细化至1.25Å的分辨率。用电子顺磁共振波谱法证实铁是TfSOD的金属辅因子。TfSOD-Fe3+/TfSOD-Fe2+氧化还原对的电池电势(Em)被确定为287mV
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引用次数: 0
The formation of Fe3+-doxycycline complex is pH dependent: implications to doxycycline bioavailability Fe3+-强力霉素复合物的形成是pH依赖性的:对强力霉素生物利用度的影响
IF 3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-09-01 DOI: 10.1007/s00775-023-02018-w
Jelena Korać Jačić, Milena Dimitrijević, Danica Bajuk-Bogdanović, Dalibor Stanković, Slađana Savić, Ivan Spasojević, Milica R. Milenković

The interactions of drugs with iron are of interest in relation to the potential effects of iron-rich foods and iron supplements on sorption and bioavailability. Doxycycline (DOX), a member of the tetracycline class of broad-spectrum antibiotics, is frequently administered by oral route. In the digestive tract, DOX can be exposed to iron at different pH values (stomach pH 1.5–4, duodenum pH 5–6, distal jejunum and ileum pH 7–8). In relation to this, we analyzed the impact of pH on Fe3+-DOX complex formation. The optimal conditions for Fe3+-DOX complex formation are pH = 4 and [Fe3+]/[DOX] = 6 molar ratio. HESI-MS showed that Fe3+-DOX complex has 1:1 stoichiometry. Raman spectra of Fe3+-DOX complex indicate the presence of two Fe3+-binding sites in DOX structure: tricarbonylamide group of ring A and phenolic-diketone oxygens of BCD rings. The Fe3+-DOX complex formed at pH = 4 is less susceptible to oxidation than DOX at this pH. The increase of pH induces the decomposition of Fe3+-DOX complex without oxidative degradation of DOX. The pH dependence of Fe3+-DOX complex formation may promote unwanted effects of DOX, impeding the absorption that mainly takes place in duodenum. This could further result in higher concentrations in the digestive tract and to pronounced impact on gut microbiota.

Graphical abstract

药物与铁的相互作用与富含铁的食物和铁补充剂对吸附和生物利用度的潜在影响有关。多西环素(DOX)是四环素类广谱抗生素中的一种,经常通过口服给药。在消化道中,DOX可以暴露于不同pH值的铁(胃pH为1.5-4,十二指肠pH为5-6,空肠远端和回肠pH为7-8)。与此相关,我们分析了pH对Fe3+-DOX络合物形成的影响。形成Fe3+-DOX络合物的最佳条件是pH = 4和[Fe3+]/[DOX] = 6摩尔比。HESI-MS结果表明,Fe3+-DOX配合物的化学计量为1:1。Fe3+-DOX配合物的拉曼光谱表明,在DOX结构中存在两个Fe3+结合位点:A环的三羰基酰胺基和BCD环的酚二酮氧。在pH下形成的Fe3+-DOX络合物 = 在该pH下,4比DOX更不易氧化。pH的增加诱导了Fe3+-DOX复合物的分解,而DOX没有氧化降解。Fe3+-DOX复合物形成的pH依赖性可能会促进DOX的不良作用,阻碍主要发生在十二指肠的吸收。这可能会进一步导致消化道中的浓度升高,并对肠道微生物群产生明显影响。图形摘要
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引用次数: 0
期刊
Journal of Biological Inorganic Chemistry
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