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Flexible active-site loops fine-tune substrate specificity of hyperthermophilic metallo-oxidases 灵活的活性位环可微调嗜热金属氧化酶的底物特异性。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-16 DOI: 10.1007/s00775-023-02040-y
Vânia Brissos, Patrícia T. Borges, Ferran Sancho, Maria Fátima Lucas, Carlos Frazão, Felipe Conzuelo, Lígia O. Martins

Hyperthermophilic (‘superheat-loving’) archaea found in high-temperature environments such as Pyrobaculum aerophilum contain multicopper oxidases (MCOs) with remarkable efficiency for oxidizing cuprous and ferrous ions. In this work, directed evolution was used to expand the substrate specificity of P. aerophilum McoP for organic substrates. Six rounds of error-prone PCR and DNA shuffling followed by high-throughput screening lead to the identification of a hit variant with a 220-fold increased efficiency (kcat/Km) than the wild-type for 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) without compromising its intrinsic activity for metal ions. The analysis of the X-ray crystal structure reveals four proximal mutations close to the T1Cu active site. One of these mutations is within the 23-residues loop that occludes this site, a distinctive feature of prokaryotic MCOs. The increased flexibility of this loop results in an enlarged tunnel and one additional pocket that facilitates bulky substrate-enzyme interactions. These findings underscore the synergy between mutations that modulate the dynamics of the active-site loop enabling enhanced catalytic function. This study highlights the potential of targeting loops close to the T1Cu for engineering improvements suitable for biotechnological applications.

Graphical Abstract

在高温环境中发现的嗜热古细菌(如嗜气梭杆菌)含有多铜氧化酶(MCOs),可高效氧化亚铜和亚铁离子。本研究利用定向进化技术扩大了嗜水气荚膜杆菌 McoP 对有机底物的特异性。经过六轮易出错的 PCR 和 DNA 洗牌以及高通量筛选,最终确定了一个命中变体,其对 2,2'-偶氮-双(3-乙基苯并噻唑啉-6-磺酸)(ABTS)的氧化效率(kcat/Km)比野生型提高了 220 倍,而且不影响其对金属离子的固有活性。对 X 射线晶体结构的分析显示,在 T1Cu 活性位点附近有四个近端突变。其中一个突变位于封闭该位点的 23 个氨基酸环路中,这是原核 MCO 的一个显著特征。这个环的灵活性增加,导致隧道扩大,并多了一个口袋,有利于大块底物与酶的相互作用。这些发现强调了调节活性位点环动态的突变与增强催化功能之间的协同作用。这项研究强调了针对靠近 T1Cu 的环路进行工程改进以适用于生物技术应用的潜力。
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引用次数: 0
Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells 用 pluronic® F-127 封装的溶酶体靶向钌(II)复合物可诱导 A549 细胞癌变。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-08 DOI: 10.1007/s00775-023-02039-5
Nanlian Pan, Yuqing Zhang, Minying Huang, Zhijun Liang, Yao Gong, Xide Chen, Yuling Li, Ciling Wu, Zunnan Huang, Jing Sun

Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

Graphical abstract

过渡金属配合物具有独特的纳米颗粒封装特性和显著的癌细胞毒性,已成为铂类抗肿瘤药物的潜在替代品。在此,我们报告了引入 5-氟尿嘧啶配体的三种新型钌配合物的合成、表征和抗肿瘤活性。值得注意的是,将其中一种金属复合物 Ru3 封装在 pluronic® F-127 胶束(Ru3-M)中可将 Ru3 对 A549 细胞的细胞毒性显著增强四倍。为了确定 Ru3-M 细胞毒性的机制,还进行了其他体外实验,结果表明用溶酶体靶向 Ru3-M 处理 A549 细胞会引发氧化应激,诱导线粒体膜电位去极化,并大幅降低细胞内 ATP 水平。综上所述,这些结果表明,Ru3-M 主要通过一种称为 "癌变 "的非凋亡途径杀死细胞,观察到的 Ru3-M 诱导的细胞形态变化(包括细胞膜潮红、细胞肿胀和细胞质空泡化)就是证明。反过来,这些变化又会导致细胞骨架崩溃,并激活具有已知致癌功能的 porimin 和 calpain1 蛋白,从而将这种致癌过程与其他细胞死亡过程区分开来。总之,Ru3-M 是一种潜在的抗癌剂,它能通过一种新的机制杀死 A549 细胞,该机制涉及 Ru(II)复合物通过癌变引发细胞死亡。
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引用次数: 0
Phototoxicity of cyclometallated Ir(III) complexes bearing a thio-bis-benzimidazole ligand, and its monodentate analogue, as potential PDT photosensitisers in cancer cell killing 含硫双苯并咪唑配体的环金属化铱(III)配合物及其单齿类似物的光毒性,可作为潜在的光致发光光敏剂杀死癌细胞。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-06 DOI: 10.1007/s00775-023-02031-z
Marta Martínez-Alonso, Callum G. Jones, James D. Shipp, Dimitri Chekulaev, Helen E. Bryant, Julia A. Weinstein

Two novel cyclometallated iridium(III) complexes have been prepared with one bidentate or two monodentate imidazole-based ligands, 1 and 2, respectively. The complexes showed intense emission with long lifetimes of the excited state. Femtosecond transient absorption experiments established the nature of the lowest excited state as 3IL state. Singlet oxygen generation with good yields (40% for 1 and 82% for 2) was established by detecting 1O2 directly, through its emission at 1270 nm. Photostability studies were also performed to assess the viability of the complexes as photosensitizers (PS) for photodynamic therapy (PDT). Complex 1 was selected as a good candidate to investigate light-activated killing of cells, whilst complex 2 was found to be toxic in the dark and unstable under light. Complex 1 demonstrated high phototoxicity indexes (PI) in the visible region, PI > 250 after irradiation at 405 nm and PI > 150 at 455 nm, in EJ bladder cancer cells.

我们制备了两种新型环金属化铱(III)配合物,它们分别含有一种双齿或两种单齿咪唑配体 1 和 2。这些配合物显示出强烈的发射,激发态的寿命很长。飞秒瞬态吸收实验确定了最低激发态为 3IL 态。通过直接检测 1O2 在 1270 纳米波长处的发射,确定了单线态氧的生成量(1 为 40%,2 为 82%)。此外,还进行了光稳定性研究,以评估这些复合物作为光敏剂(PS)用于光动力疗法(PDT)的可行性。复合物 1 被选为研究光激活细胞杀伤作用的理想候选物质,而复合物 2 在黑暗中有毒,在光照下不稳定。复合物 1 在可见光区域对 EJ 膀胱癌细胞表现出较高的光毒性指数(PI),在 405 纳米波长下照射后 PI > 250,在 455 纳米波长下照射后 PI > 150。
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引用次数: 0
Ruthenium(II) complex with 2-mercaptothiazoline ligand induces selective cytotoxicity involving DNA damage and apoptosis in melanoma cells 钌(II)与 2-巯基噻唑啉配体的复合物可诱导黑色素瘤细胞产生选择性细胞毒性,包括 DNA 损伤和细胞凋亡。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-05 DOI: 10.1007/s00775-023-02036-8
Matheus Reis Santos de Melo, Arthur Barcelos Ribeiro, Gabriela Fernandes, Iara Silva Squarisi, Marcela de Melo Junqueira, Alzir Azevedo Batista, Monize Martins da Silva, Denise Crispim Tavares

Melanoma is the most aggressive and lethal type of skin cancer due to its characteristics such as high metastatic potential and low response rate to existing treatment modalities. In this way, new drug prototypes are being studied to solve the problem of treating patients with melanoma. Among these, ruthenium-based metallopharmaceuticals may be promising alternatives due to their antitumor characteristics and low systemic toxicity. In this context, the present study evaluated the antineoplastic effect of the ruthenium complex [Ru(mtz)(dppe)2]PF6-2-mercaptothiazoline-di-1,2-bis(diphenylphosphine) ethaneruthenium(II), namely RuMTZ, on human melanoma (A-375) and murine (B16-F10) cells, considering different approaches. Through XTT colorimetric and clonogenic efficiency assays, the complex revealed the selective cytotoxic activity, with the lowest IC50 (0.4 µM) observed for A375 cells. RuMTZ also induced changes in cell morphology, increased cell population in the sub-G0 phase and inhibiting cell migration. The levels of γH2AX and cleaved caspase 3 proteins were increased in both cell lines treated with RuMTZ. These findings indicated that the cytotoxic activity of RuMTZ on melanoma cells is related, at least in part, to the induction of DNA damage and apoptosis. Therefore, RuMTZ exhibited promising antineoplastic activity against melanoma cells.

Graphical abstract

黑色素瘤是最具侵袭性和致命性的皮肤癌类型,其特点是转移潜力大,对现有治疗方法的反应率低。因此,人们正在研究新的药物原型,以解决黑色素瘤患者的治疗问题。其中,基于钌的金属药物因其抗肿瘤特性和低全身毒性,可能是很有前景的替代药物。在此背景下,本研究采用不同的方法评估了钌复合物[Ru(mtz)(dppe)2]PF6-2-巯基噻唑啉-二-1,2-双(二苯基膦)乙钌(II),即 RuMTZ 对人类黑色素瘤(A-375)和小鼠(B16-F10)细胞的抗肿瘤作用。通过 XTT 比色法和克隆效率测定,该复合物显示出选择性细胞毒性活性,对 A375 细胞的 IC50 最低(0.4 µM)。RuMTZ 还能诱导细胞形态发生变化、增加亚 G0 期细胞数量并抑制细胞迁移。用 RuMTZ 处理的两种细胞系中,γH2AX 和裂解的 caspase 3 蛋白水平都有所升高。这些发现表明,RuMTZ 对黑色素瘤细胞的细胞毒性活性至少部分与诱导 DNA 损伤和细胞凋亡有关。因此,RuMTZ 对黑色素瘤细胞具有良好的抗肿瘤活性。
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引用次数: 0
Effects of the tetravanadate [V4O12]4− anion on the structural, magnetic, and biological properties of copper/phenanthroline complexes 四钒酸盐 [V4O12]4- 阴离子对铜/菲罗啉配合物的结构、磁性和生物特性的影响。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-04 DOI: 10.1007/s00775-023-02035-9
Eduardo Sánchez-Lara, Roberto Favela, Kitze Tzian, Brian Monroy-Torres, Adriana Romo-Pérez, María Teresa Ramírez-Apan, Marcos Flores-Alamo, Antonio Rodríguez-Diéguez, Javier Cepeda, Ivan Castillo

The aim to access linked tetravanadate [V4O12]4− anion with mixed copper(II) complexes, using α-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]·9H2O (1) [Cu(dmb)(Lys)]2[V4O12]·8H2O (2), [Cu(dmp)2][V4O12]·C2H5OH·11H2O (3), and [Cu(dmp)(Gly)Cl]·2H2O (4), where dmb = 4,4′-dimethioxy-2,2′-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V4O12]4− anion is functionalized with mixed copper(II) units in 1 and 2; while in 3, it acts as a counterion of two [Cu(dmp)]2+ units. Compound 4 crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cu⋯O/Cu⋯Cu bridges. Stability studies of water-soluble 3 and 4 by UV–Vis spectroscopy in cell culture medium confirmed the robustness of 3, while 4 appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)2]+ that was also identified by electrospray ionization mass spectrometry at m/z = 479. The in vitro cytotoxicity activity of 3 and 4 was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound 3 with an IC50 value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium–copper(II) systems.

Graphical abstract

目的是利用α-氨基酸和菲罗啉衍生配体,将四钒酸盐[V4O12]4-阴离子与混合铜(II)配合物连接起来、形成了四种铜(II)配合物 [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]-9H2O (1) [Cu(dmb)(Lys)]2[V4O12]-8H2O (2)、[Cu(dmp)2][V4O12]-C2H5OH-11H2O(3)和[Cu(dmp)(Gly)Cl]-2H2O(4),其中 dmb = 4,4'-二甲氧基-2,2'-联吡啶;Gly = 甘氨酸;Lys = 赖氨酸;dmp = 2,9-二甲基-1,10-菲罗啉。在 1 和 2 中,[V4O12]4- 阴离子与混合铜(II)单元官能化;而在 3 中,它是两个[Cu(dmp)]2+ 单元的反离子。化合物 4 的结晶单元不包含钒簇。所有化合物都存在由 Cu⋯O/Cu⋯Cu 桥产生的磁耦合。通过紫外可见光谱对水溶性 3 和 4 在细胞培养基中的稳定性进行研究,证实了 3 的稳健性,而 4 似乎会随着时间的推移而发生配体扰乱,部分形成稳定的物种 [Cu(dmp)2]+,电喷雾电离质谱法也在 m/z = 479 处对其进行了鉴定。在六种癌细胞系中测定了 3 和 4 的体外细胞毒性活性;健康细胞系 COS-7 也被纳入其中进行比较。MCF-7 细胞对化合物 3 更为敏感,其 IC50 值为 12 ± 1.2 nmol。在 TBARS 试验中,受试化合物未出现脂质过氧化反应,排除了通过活性氧形成作用机制的可能性。在使用 MCF-7、PC-3 和 SKLU-1 细胞系进行的伤口愈合试验中,两种化合物在 5 µM 的浓度下都能抑制细胞迁移,这为研究钒-铜(II)混合体系的抗转移效应打开了一扇新窗口。
{"title":"Effects of the tetravanadate [V4O12]4− anion on the structural, magnetic, and biological properties of copper/phenanthroline complexes","authors":"Eduardo Sánchez-Lara,&nbsp;Roberto Favela,&nbsp;Kitze Tzian,&nbsp;Brian Monroy-Torres,&nbsp;Adriana Romo-Pérez,&nbsp;María Teresa Ramírez-Apan,&nbsp;Marcos Flores-Alamo,&nbsp;Antonio Rodríguez-Diéguez,&nbsp;Javier Cepeda,&nbsp;Ivan Castillo","doi":"10.1007/s00775-023-02035-9","DOIUrl":"10.1007/s00775-023-02035-9","url":null,"abstract":"<div><p>The aim to access linked tetravanadate [V<sub>4</sub>O<sub>12</sub>]<sup>4−</sup> anion with mixed copper(II) complexes, using <i>α</i>-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH<sub>2</sub>)]<sub>2</sub>[Cu(dmb)(Gly)]<sub>2</sub>[V<sub>4</sub>O<sub>12</sub>]·9H<sub>2</sub>O (<b>1</b>) [Cu(dmb)(Lys)]<sub>2</sub>[V<sub>4</sub>O<sub>12</sub>]·8H<sub>2</sub>O (<b>2</b>), [Cu(dmp)<sub>2</sub>][V<sub>4</sub>O<sub>12</sub>]·C<sub>2</sub>H<sub>5</sub>OH·11H<sub>2</sub>O (<b>3</b>), and [Cu(dmp)(Gly)Cl]·2H<sub>2</sub>O (<b>4</b>), where dmb = 4,4′-dimethioxy-2,2′-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V<sub>4</sub>O<sub>12</sub>]<sup>4−</sup> anion is functionalized with mixed copper(II) units in <b>1</b> and <b>2</b>; while in <b>3</b>, it acts as a counterion of two [Cu(dmp)]<sup>2+</sup> units. Compound <b>4</b> crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cu⋯O/Cu⋯Cu bridges. Stability studies of water-soluble <b>3</b> and <b>4</b> by UV–Vis spectroscopy in cell culture medium confirmed the robustness of <b>3</b>, while <b>4</b> appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)<sub>2</sub>]<sup>+</sup> that was also identified by electrospray ionization mass spectrometry at <i>m</i>/<i>z</i> = 479. The in vitro cytotoxicity activity of <b>3</b> and <b>4</b> was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound <b>3</b> with an IC<sub>50</sub> value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium–copper(II) systems.</p><h3>Graphical abstract</h3>\u0000<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":"29 1","pages":"139 - 158"},"PeriodicalIF":2.7,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11001746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139085429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The deposition of lanthanum carbonate may activate macrophages to induce gastrointestinal mucosal injury in patients with chronic kidney disease: an in vitro caco-2/THP-1 macrophage coculture model study 碳酸镧沉积可能激活巨噬细胞,诱发慢性肾病患者胃肠道粘膜损伤:体外 caco-2/THP-1 巨噬细胞共培养模型研究。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-12-26 DOI: 10.1007/s00775-023-02033-x
Ya-Ju Song, Hui-Xue Liu, Xiao-Gai Yang

The aim of this study was to investigate the effect and possible underlying mechanism of La2(CO3)3 deposition on GI mucosal inflammation. Our results showed that La2(CO3)3 can dissolve in artificial gastric fluids and form lanthanum phosphate (LaPO4) precipitates with an average size of about 1 μm. To mimic the intestinal mucosa and epithelial barrier, we established a Caco-2/THP-1 macrophage coculture model and a Caco-2 monoculture model, respectively. Our findings demonstrated that the medium of THP-1 macrophages stimulated by LaPO4 particles can damage the Caco-2 monolayer integrity in the coculture model, while the particles themselves had no direct impact on the Caco-2 monolayer integrity in the monoculture model. We measured values of trans-epithelial electrical resistance and detected images using a laser scanning confocal microscope. These results indicate that continuous stimulation of LaPO4 particles on macrophages can lead to a disruption of intestinal epithelium integrity. In addition, LaPO4 particles could stimulate THP-1 macrophages to secrete both IL-1β and IL-8. Although LaPO4 particles can also promote Caco-2 cells to secrete IL-8, the secretion was much lower than that produced by THP-1 macrophages. In summary, the deposition of La2(CO3)3 has been shown to activate macrophages and induce damage to intestinal epithelial cells, which may exacerbate inflammation in patients with chronic kidney disease. Therefore, patients taking lanthanum carbonate, especially those with gastrointestinal mucosal inflammation, should be mindful of the potential for drug deposition in the GI system.

Graphical abstract

A schematic diagram of the effect and possible underlying mechanism of the deposition of La2(CO3)3 on GI mucosal inflammation. 

本研究旨在探讨 La2(CO3)3 沉积对消化道粘膜炎症的影响及其可能的内在机制。结果表明,La2(CO3)3能溶解于人工胃液中,并形成平均大小约为1微米的磷酸镧(LaPO4)沉淀物。为了模拟肠粘膜和上皮屏障,我们分别建立了 Caco-2/THP-1 巨噬细胞共培养模型和 Caco-2 单培养模型。我们的研究结果表明,在共培养模型中,LaPO4 颗粒刺激 THP-1 巨噬细胞的培养基会破坏 Caco-2 单层的完整性,而在单培养模型中,颗粒本身对 Caco-2 单层的完整性没有直接影响。我们测量了跨上皮电阻值,并使用激光扫描共聚焦显微镜检测了图像。这些结果表明,LaPO4 颗粒对巨噬细胞的持续刺激可导致肠上皮完整性的破坏。此外,LaPO4 颗粒还能刺激 THP-1 巨噬细胞分泌 IL-1β 和 IL-8。虽然 LaPO4 颗粒也能促进 Caco-2 细胞分泌 IL-8,但其分泌量远低于 THP-1 巨噬细胞。总之,La2(CO3)3 的沉积已被证明可激活巨噬细胞并诱发肠上皮细胞损伤,这可能会加剧慢性肾病患者的炎症。因此,服用碳酸镧的患者,尤其是有胃肠道粘膜炎症的患者,应注意药物在胃肠道系统沉积的可能性。La2(CO3)3 对胃肠道粘膜炎症沉积的影响和可能的内在机制示意图。
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引用次数: 0
Desulfurization of thiosemicarbazones: the role of metal ions and biological implications 硫代氨基羰基化合物的脱硫:金属离子的作用和生物学意义。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-12-26 DOI: 10.1007/s00775-023-02037-7
Alondra Jiménez-Pérez, Sandra Fernández-Fariña, Rosa Pedrido, Javier García-Tojal

Thiosemicarbazones are biologically active substances whose structural formula is formed by an azomethine, an hydrazine, and a thioamide fragments, to generate a R2C=N–NR–C(=S)–NR2 backbone. These compounds often act as ligands to generate highly stable metal–organic complexes. In certain experimental conditions, however, thiosemicarbazones undergo reactions leading to the cleavage of the chain. Sometimes, the breakage involves desulfurization processes. The present work summarizes the different chemical factors that influence the desulfurization reactions of thiosemicarbazones, such as pH, the presence of oxidant reactants or the establishment of redox processes as those electrochemically induced, the effects of the solvent, the temperature, and the electromagnetic radiation. Many of these reactions require coordination of thiosemicarbazones to metal ions, even those present in the intracellular environment. The nature of the products generated in these reactions, their detection in vivo and in vitro, together with the relevance for the biological activity of these compounds, mainly as antineoplastic agents, is discussed.

Graphical abstract

硫代氨基甲酰肼是一种具有生物活性的物质,其结构式由一个偶氮甲烷、一个肼和一个硫代酰胺片段组成,从而产生一个 R2C=N-NR-C(=S)-NR2 主干。这些化合物通常作为配体生成高度稳定的金属有机络合物。然而,在某些实验条件下,硫代氨基甲酸盐会发生导致链断裂的反应。有时,断裂涉及脱硫过程。本研究总结了影响硫代氨基脲脱硫反应的各种化学因素,如 pH 值、氧化剂反应物的存在或电化学诱导的氧化还原过程的建立、溶剂的影响、温度和电磁辐射。其中许多反应需要硫代氨基甲酸与金属离子配位,即使是存在于细胞内环境中的金属离子也不例外。本文讨论了这些反应中生成的产物的性质、它们在体内和体外的检测情况,以及这些化合物的生物活性(主要是作为抗肿瘤药物)的相关性。
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引用次数: 0
Synthesis, crystal structures, and biological activity of aroylhydrazone di-m-chlorobenzyltin complexes 甲酰腙二间氯苄锡复合物的合成、晶体结构和生物活性。
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-12-23 DOI: 10.1007/s00775-023-02038-6
Wujiu Jiang, Pengfei Zhou, Le Chen, Weiwei Fu, Yuxing Tan

Six aroylhydrazone di-m-chlorobenzyltin complexes {[X-C6H4(O)C=N–N=C(Me)COO](MeOH)(m-Cl-C6H4CH2)2Sn}2 (X = p-Me- (1), p-MeO- (2), pt-Bu- (3), p-NO2- (4), p-OH- (5) or o-OH- (6)) were synthesized and characterized by HRMS (high-resolution mass spectrometry), NMR (nuclear magnetic resonance spectroscopy), IR (Fourier transform infrared spectroscopy), and TGA (thermogravimetric analysis) techniques. The molecular structure of complexes 16 was confirmed by single-crystal X-ray crystallography. The structure of complexes showed a distorted pentagonal bipyramidal configuration around the tin atom center, and the ligands adopted a tridentate chelating mode. Fascinatingly, either one-dimensional infinite chain structures or two-dimensional network structures were observed in the complexes through hydrogen bonds. Complex 2 has the strongest inhibitory effect on MCF7 and HepG2 cell proliferation, its effect was superior to that of the positive control drug cisplatin. The interaction of ct-DNA (calf-thymus DNA) with complex 2 was explored using UV absorption (ultraviolet absorption) and fluorescence spectroscopy. Complex 2 exhibited a moderate affinity for ct-DNA through intercalation modes. The interaction of complex 2 with ct-DNA has also been supported by molecular docking studies.

Graphical abstract

通过 HRMS(高分辨率质谱)、NMR(核磁共振波谱)和 o-OH- (6) 等方法合成并表征了六种甲酰基腙二间氯苄锡配合物 {[X-C6H4(O)C=N-N=C(Me)COO](MeOH)(m-Cl-C6H4CH2)2Sn}2 (X = p-Me- (1)、p-MeO- (2)、p-t-Bu- (3)、p-NO2- (4)、2Sn}2 (X = p-Me- (1)、p-MeO- (2)、p-t-Bu- (3)、p-NO2- (4)、p-OH- (5) 或 o-OH- (6))的合成,并通过 HRMS(高分辨率质谱)、NMR(核磁共振光谱)、IR(傅立叶变换红外光谱)和 TGA(热重分析)技术对其进行了表征。单晶 X 射线晶体学证实了复合物 1-6 的分子结构。配合物的结构以锡原子为中心呈扭曲的五角双锥构型,配体采用三叉螯合模式。有趣的是,通过氢键,在配合物中观察到了一维无限链结构或二维网络结构。复合物 2 对 MCF7 和 HepG2 细胞增殖的抑制作用最强,其效果优于阳性对照药物顺铂。利用紫外线吸收和荧光光谱分析了ct-DNA(小牛胸腺 DNA)与复合物 2 的相互作用。通过插层模式,复合物 2 与ct-DNA 的亲和力适中。分子对接研究也证实了复合物 2 与 ct-DNA 的相互作用。
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引用次数: 0
Bioactive apatite–wollastonite glass ceramics coating on metallic titanium for biomedical applications: effect of boron 用于生物医学应用的金属钛上的生物活性磷灰石-硅灰石玻璃陶瓷涂层:硼的影响
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-12-20 DOI: 10.1007/s00775-023-02032-y
Eren Yılmaz, Serbülent Türk, Alican Bahadır Semerci, Mine Kırkbınar, Erhan İbrahimoğlu, Fatih Çalışkan

Metallic titanium (Ti) implant surfaces need improvement for bioproperties and antibacterial behavior. For this purpose, a new boron-doped bioactive apatite–wollastonite (AW) coating was successfully developed on the Ti plate surface. The effects of boron addition on the microstructure, mechanical properties, and bioproperties of the AW coating were investigated. With the addition of boron (B), the AW coating morphology became less porous and compact. In terms of bio properties, the rate of apatite formation increased with the addition of B, and the cell viability rate increased from approximately 66–81%. B addition increased the elastic modulus of the AW coating from about 24–46 GPa and increased its hardness about 2.5 times. In addition, while no antibacterial activity was observed in the AW coating, the addition of boron slightly introduced antibacterial properties. The novel AW/B composite coating obtained is promising for Ti implant surfaces.

Graphical abstract

金属钛(Ti)植入物表面的生物特性和抗菌性能需要改进。为此,在钛板表面成功开发了一种新型掺硼生物活性磷灰石-硅灰石(AW)涂层。研究了添加硼元素对 AW 涂层的微观结构、机械性能和生物特性的影响。随着硼(B)的加入,AW 涂层的形态变得疏松而紧密。在生物特性方面,磷灰石的形成率随着硼的添加而增加,细胞存活率从大约 66% 增加到 81%。硼的添加使 AW 涂层的弹性模量从 24-46 GPa 增加,硬度增加了约 2.5 倍。此外,虽然在 AW 涂层中没有观察到抗菌活性,但硼的添加略微引入了抗菌特性。所获得的新型 AW/B 复合涂层有望用于钛种植体表面。
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引用次数: 0
Anti-toxoplasma activity and DNA-binding of copper(II) and zinc(II) coordination compounds with 5-nitroimidazole-based ligands 含 5-硝基咪唑配体的铜(II)和锌(II)配位化合物的抗支原体活性和 DNA 结合力
IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-12-15 DOI: 10.1007/s00775-023-02029-7
Rubí Navarro-Peñaloza, Jhony Anacleto-Santos, Norma Rivera-Fernández, Francisco Sánchez-Bartez, Isabel Gracia-Mora, Ana B. Caballero, Patrick Gamez, Norah Barba-Behrens

Tetrahedral copper(II) and zinc(II) coordination compounds from 5-nitroimidazole derivatives, viz. 1-(2-chloroethyl)-2-methyl-5-nitroimidazole (cenz) and ornidazole 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (onz), were synthesized and spectroscopically characterized. Their molecular structures were determined by X-ray diffraction studies. The complexes [Cu(onz)2X2], [Zn(onz)2X2], [Cu(cenz)2X2] and [Zn(cenz)2X2] (X = Cl, Br), are stable in solution and exhibit positive LogD7.4 values that are in the range for molecules capable of crossing the cell membrane via passive difussion. Their biological activity against Toxoplasma gondi was investigated, and IC50 and lethal dose (LD50) values were determined. The ornidazole copper(II) compounds showed very good antiparasitic activity in its tachyzoite morphology. The interaction of the coordination compounds with DNA was examined by circular dichroism, fluorescence (using intercalating ethidium bromide and minor groove binding Hoechst 33258) and UV–Vis spectroscopy. The copper(II) compounds interact with the minor groove of the biomolecule, whereas weaker electrostatic interactions take place with the zinc(II) compounds. The spectroscopic data achieved for the two series of complexes (namely with copper(II) and zinc(II) as metal center) agree with the respective DNA-damage features observed by gel electrophoresis.

Graphical abstract

从 5-硝基咪唑衍生物(即 1-(2-氯乙基)-2-甲基-5-硝基咪唑(cenz)和 1-(3-氯-2-羟基丙基)-2-甲基-5-硝基咪唑(onz))合成了四面体铜(II)和锌(II)配位化合物,并对其进行了光谱表征。通过 X 射线衍射研究确定了它们的分子结构。[Cu(onz)2X2]、[Zn(onz)2X2]、[Cu(cenz)2X2]和[Zn(cenz)2X2](X- = Cl、Br)复合物在溶液中稳定,并显示出正 LogD7.4 值,处于能够通过被动扩散作用穿过细胞膜的分子的范围内。研究人员考察了它们对弓形虫的生物活性,并测定了 IC50 和致死剂量 (LD50) 值。奥硝唑铜(II)化合物在弓形虫形态上显示出非常好的抗寄生虫活性。配位化合物与 DNA 的相互作用是通过圆二色性、荧光(使用插入型溴化乙锭和小沟结合型 Hoechst 33258)和紫外可见光谱进行检测的。铜(II)化合物与生物大分子的次凹槽相互作用,而锌(II)化合物的静电作用较弱。两个系列复合物(即以铜(II)和锌(II)为金属中心的复合物)的光谱数据与凝胶电泳观察到的 DNA 损伤特征一致。
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引用次数: 0
期刊
Journal of Biological Inorganic Chemistry
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