Journal of Inorganic Biochemistry最新文献_第4页

Organometallic and coordination gold(I)-azole drugs compounds: Synthesis, characterization, antitumor evaluation, and interactions with biomolecules 有机金属和配位金(I)-唑类药物化合物：合成、表征、抗肿瘤评价和与生物分子的相互作用

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-08 DOI: 10.1016/j.jinorgbio.2025.113142

Camila Aparecida da Silva dos Reis Condé , Katherine Lima Bruno , Camilla Barbosa Calçado , Giset Y. Sánchez Delgado , Willian Xerxes Coelho Oliveira , Heveline Silva , Maribel Navarro

According to the World Health Organization, an estimated 9.7 million people died from cancer worldwide in 2024. Considering this devastating scenario, our strategy is to search for gold(I) compounds with the potential to be used as anticancer drugs. We have synthesized the organometallic gold(I)-NHC methylclotrimazole (CTZMe, 1) and gold(I)-NHC methylketoconazole (KTZMe, 2), as well as the gold(I)-CTZ (clotrimazole)/KTZ (ketoconazole) coordination compounds (3–4). Their structures were confirmed through full characterization using analytical and spectroscopic techniques including elemental analysis, molar conductivity, infrared (IR), ultraviolet–visible (UV–Vis), magnetic nuclear resonance (NMR), electrospray ionization mass spectrometry (ESI–MS), and X-ray diffraction of a single crystal for complex 1, with additional support from theoretical calculations. Gold(I) complexes (1–4) were tested against tumor cell lines (MDA-MB-231 and 4 T1) and in a normal cell line (MCF-10 A), revealing that complexes 1–4 were generally more active and selective than free imidazole antifungal drugs and their imidazolium salts, with compound 1 being the most active. These gold complexes (1–4) were found to interact with DNA; however, this was not the main target. Instead, they displayed substantial interaction with glutathione, as determined by colorimetric assay and NMR-monitored analysis, suggesting preferential interaction with thiol-containing enzymes such as Thioredoxin Reductase (TrxR). Molecular docking suggested two possible modes of TrxR inhibition: (i) redox-center blockade by KTZ-containing compounds (2 and 4) and (ii) direct AuS binding by CTZ-based compounds (1 and 3), particularly for the most active complex 1, which might contribute to its higher anticancer activity.

根据世界卫生组织的数据，2024年全球约有970万人死于癌症。考虑到这种毁灭性的情况，我们的策略是寻找有可能用作抗癌药物的金(I)化合物。我们合成了有机金属金(I)-NHC甲基氯三唑（CTZMe, 1）和金(I)-NHC甲基酮康唑（KTZMe, 2），以及金(I)-CTZ（氯三唑）/KTZ（酮康唑）配位化合物（3-4）。通过分析和光谱技术，包括元素分析、摩尔电导率、红外（IR）、紫外-可见（UV-Vis）、核磁共振（NMR）、电喷雾质谱（ESI-MS）和x射线单晶衍射，以及理论计算的额外支持，确认了它们的结构。金(I)配合物（1 - 4）对肿瘤细胞系（MDA-MB-231和4t1）和正常细胞系（mcf - 10a）的作用测试表明，配合物1 - 4通常比游离咪唑抗真菌药物及其咪唑盐更具活性和选择性，其中化合物1活性最强。这些金配合物（1-4）被发现与DNA相互作用；然而，这并不是主要目标。相反，通过比色法和核磁共振监测分析，它们显示出与谷胱甘肽的实质性相互作用，表明它们与含硫醇的酶（如硫氧还蛋白还原酶（TrxR））优先相互作用。分子对接提示了两种可能的TrxR抑制模式：(i)含有ktz的化合物（2和4）阻断氧化还原中心；（ii）基于ctz的化合物（1和3）直接结合AuS，特别是最活跃的复合物1，这可能有助于其更高的抗癌活性。

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引用次数: 0

Mono-fluorotryptophans as probes of proton-coupled electron transfer in biology 单氟色氨酸作为生物中质子耦合电子转移的探针。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-08 DOI: 10.1016/j.jinorgbio.2025.113141

Jane Fu , Nejc Nagelj , Matthew C. Drummer , Kristopher G. Reynolds , Dave Y. Song , JoAnne Stubbe , Daniel G. Nocera

Tryptophan radicals are relevant to charge transport and catalysis in several enzymes. The radical is produced by the removal of an electron and proton from tryptophan. Despite its prevalence, tools to probe tryptophan radicals in biological systems remain limited. Fluorination of the indole ring of tryptophan induces changes in the redox potential, pK_a and absorption spectrum, thus making fluorotryptophans attractive residues to probe the transient role of tryptophan radicals in biological systems. A series of N-acylated mono-fluorotryptophan amide analogs have been synthesized. Fluorine substitution at the 4 to 7 positions on the indole ring expands the a pK_a of the indole proton from 4.6 to 3.8–4.0 and a shift in reduction potential of 70 to 115 mV in the pH independent region (pH < 4) and 33 to 72 mV in the pH dependent regime that is accessible to most proteins (pH 6 to 9). Spectral shifts between 550 and 620 nm for the fluorotryptophan radical cation and between 495 and 550 nm for the neutral fluorotryptophan radical, respectively, allow their transient formation to be differentiated from background tryptophans in protein systems. The red shift of the radical cation as compared to the neutral radical is captured by DFT calculations and is shown to arise primarily from the stabilization of the radical cation SOMO. With the emergence of genetic code expansion techniques for incorporating fluorotryptophans in proteins, the mono-fluorotryptophans reported herein will be useful unnatural amino acids for examining tryptophan radicals in biology.

色氨酸自由基与几种酶的电荷传输和催化作用有关。自由基是通过从色氨酸中除去一个电子和质子而产生的。尽管它很普遍，但在生物系统中探测色氨酸自由基的工具仍然有限。色氨酸吲哚环的氟化引起氧化还原电位、pKa和吸收光谱的变化，从而使氟色氨酸成为吸引残基，用于探索色氨酸自由基在生物系统中的瞬时作用。合成了一系列n -酰化单氟色氨酸酰胺类似物。在吲哚环上4至7位的氟取代使吲哚质子的pKa从4.6扩展到3.8-4.0，在pH无关区（pH < 4）还原电位为70至115 mV，在大多数蛋白质可达的pH依赖区（pH 6至9）还原电位为33至72 mV。荧光色氨酸阳离子的光谱位移在550 - 620 nm之间，中性荧光色氨酸自由基的光谱位移在495 - 550 nm之间，这使得它们的瞬时形成能够与蛋白质系统中的背景色氨酸区分。与中性自由基相比，自由基阳离子的红移被DFT计算捕获，并显示主要是由自由基阳离子SOMO的稳定引起的。随着将荧光色氨酸纳入蛋白质的遗传密码扩展技术的出现，本文报道的单荧光色氨酸将成为检测生物学中色氨酸自由基的有用的非天然氨基酸。

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引用次数: 0

Employing phosphonate and phosphinate ligands for prodrug development of the mitochondrial calcium uniporter inhibitor Ru265 利用膦酸盐和膦酸盐配体开发线粒体单钙转运抑制剂Ru265的前药。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-07 DOI: 10.1016/j.jinorgbio.2025.113145

Haipei Zou , Samantha N. MacMillan , Justin J. Wilson

Ru265, [Ru₂(μ-N)(NH₃)₈Cl₂]Cl₃, is a potent nanomolar inhibitor of the mitochondrial calcium uniporter (MCU), the transporter that mediates Ca²⁺ uptake into the mitochondria. This compound and related MCU inhibitors are promising therapeutic agents and chemical biology tools for studying intracellular Ca²⁺ dynamics. Axial ligand modification of these Ru-based complexes provides a facile way to tune their properties and make prodrugs. In this study, the use of axial phosphonate and phosphinate ligands was explored within this compound class, yielding [Ru₂(μ-N)(NH₃)₈(OPO(OH)Me)₂](CF₃SO₃)₃ (1) and [Ru₂(μ-N)(NH₃)₈(OPOPh₂)₂](CF₃SO₃)₃ (2). Both complexes were characterized by multinuclear NMR spectroscopy, revealing downfield shifts of the ³¹P resonances of the coordinated ligands. The crystal structure of 1 was also obtained, which confirmed coordination of the methylphosphonate ligands to the axial sites of the Ru core. The aquation of 1 and 2 were studied by NMR and UV–vis spectroscopy. Unexpectedly, compound 1 undergoes partial aquation, arresting at a final product in which only one axial methylphosphonate is displaced by water. By contrast, 2 loses both diphenylphosphinates via aquation (t_1/2 = 1.7 h) under physiological conditions. The in vitro biological investigations of 1 and 2 in HeLa cells showed that neither demonstrate high cytotoxicity nor depolarize the mitochondrial membrane potential. Both compounds exhibit nanomolar inhibitory activity against mitochondrial Ca²⁺ uptake in permeabilized HEK293T cells and modest inhibitory activity against this process in intact HeLa cells. Notably, 1 shows pH-dependent activity for MCU inhibition, with greater inhibition in more acidic conditions, while 2 shows improvement in cellular uptake efficiency.

Ru265, [Ru2(μ-N)(NH3)8Cl2]Cl3，是线粒体钙单转运体（MCU）的一种有效的纳米摩尔抑制剂，MCU是一种介导Ca2+摄取到线粒体的转运体。该化合物和相关的MCU抑制剂是研究细胞内Ca2+动力学的有前途的治疗剂和化学生物学工具。这些钌基配合物的轴向配体修饰为调整其性质和制备前药提供了一种简便的方法。本研究探索了轴向膦酸盐和膦酸盐配体在该类化合物中的应用，得到[Ru2(μ-N)(NH3)8(OPO(OH)Me)2](CF3SO3)3(1)和[Ru2(μ-N)(NH3)8(OPOPh2)2](CF3SO3)3(2)。两种配合物均通过多核核磁共振谱进行了表征，揭示了配体31P共振的下场位移。得到了1的晶体结构，证实了甲基膦酸盐配体与Ru核轴位的配位。用核磁共振和紫外-可见光谱研究了1和2的水溶液。出乎意料的是，化合物1经历了部分水合作用，最终产物中只有一个轴向甲基膦酸盐被水置换。相反，在生理条件下，2通过水化（t1/2 = 1.7 h）失去了两种二苯基膦酸盐。1和2在HeLa细胞中的体外生物学研究表明，它们都没有表现出高的细胞毒性，也没有使线粒体膜电位去极化。这两种化合物在通透化的HEK293T细胞中对线粒体Ca2+摄取表现出纳米级的抑制活性，在完整的HeLa细胞中对这一过程表现出适度的抑制活性。值得注意的是，1显示出ph依赖性的MCU抑制活性，在更酸性的条件下具有更大的抑制作用，而2显示出细胞摄取效率的提高。

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引用次数: 0

Biophysical and in silico studies on the interaction of polypyridyl ruthenium complexes with human serum albumin: Overcoming low affinity and high luminescence challenges 多吡啶钌配合物与人血清白蛋白相互作用的生物物理和硅研究：克服低亲和力和高发光挑战。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-07 DOI: 10.1016/j.jinorgbio.2025.113140

Anna Poznańska , Przemysław Gajda-Morszewski , Ilona Gurgul , Olga Mazuryk , Justyna Kalinowska-Tłuścik , Małgorzata Brindell

The concentration of free drug available for target binding is significantly influenced by its interaction with plasma proteins, primarily human serum albumin (HSA). In this study, we focused on the interactions between HSA and polypyridyl ruthenium complexes, a class of compounds known for their cytotoxic and antimetastatic properties. Since the fluorescence quenching technique for determining dissociation constants was not applicable in the studied case, a novel TRIC (temperature-related intensity change) technique was employed in combination with molecular docking to gain a deeper understanding of mutual recognition and binding. To assess the biological relevance of these interactions, we also conducted in vitro experiments, evaluating cytotoxicity and cellular uptake. Our findings revealed moderate binding (dissociation constant ranging from 0.2 to 1.2 mM) of the ruthenium complexes to HSA, resulting in a low protein-bound fraction. The result was consistent with the negligible impact of HSA observed on cytotoxicity and cellular uptake in human breast cancer MCF-7 cells. The integration of TRIC with molecular docking provided a valuable insight into metal complex-protein interaction and demonstrated a powerful strategy in medicinal chemistry, enabling the rational modulation of drug-protein interactions to optimize the pharmacokinetics of metal-based therapeutics.

可用于靶标结合的游离药物浓度受其与血浆蛋白（主要是人血清白蛋白（HSA））相互作用的显著影响。在这项研究中，我们重点研究了HSA和多吡啶基钌配合物之间的相互作用，多吡啶基钌配合物是一类以其细胞毒性和抗转移特性而闻名的化合物。由于荧光猝灭技术无法确定解离常数，因此我们采用了一种新的TRIC（温度相关强度变化）技术，结合分子对接，以加深对相互识别和结合的理解。为了评估这些相互作用的生物学相关性，我们还进行了体外实验，评估细胞毒性和细胞摄取。我们的研究结果显示，钌配合物与HSA的结合程度适中（解离常数范围为0.2至1.2 mM），导致蛋白结合率较低。结果与观察到的HSA对人乳腺癌MCF-7细胞的细胞毒性和细胞摄取的可忽略影响一致。TRIC与分子对接的结合为金属配合物-蛋白质相互作用提供了有价值的见解，并在药物化学中展示了一种强大的策略，使药物-蛋白质相互作用的合理调节能够优化金属基治疗药物的药代动力学。

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引用次数: 0

Corrigendum to ‘Activating metal sites for electron transfer and catalysis’ [Journal of Inorganic Biochemistry vol 272 (2025) 113009] “激活电子转移和催化的金属位点”的勘误表[Journal of Inorganic Biochemistry vol 272(2025) 113009]。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-07 DOI: 10.1016/j.jinorgbio.2025.113136

Edward I. Solomon , Robert R. Gipson

引用次数: 0

Forged in O2: Transition metal ions and the rise of aerobic life 在O2中锻造：过渡金属离子与有氧生命的兴起。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-07 DOI: 10.1016/j.jinorgbio.2025.113147

Kylie S. Uyeda, A.S. Borovik

The evolution of oxidative metabolism has shaped life on Earth, from ancient anaerobic microorganisms to modern eukaryotes. Central to aerobic life is the ability of metalloproteins to regulate and utilize dioxygen through tightly controlled biochemical processes. Beginning with the emergence of oxygenic photosynthesis and aerobic respiration, the pivotal roles of metalloenzymes in dioxygen activation, utilization and detoxification are then highlighted. Bridging perspectives from bioinorganic chemistry, enzymology, synthetic biology and microbiome science, we discuss how studies of biomimetic molecular complexes and natural and artificial metalloproteins illuminate the structural and functional strategies used to manage dioxygen reactivity. We further consider the systemic roles of metal ions in maintaining redox balance, shaping host-microbe interactions, and contributing to pathological outcomes when misregulated. A foundation is established for understanding the critical roles that metal ions play in dioxygen chemistry that underpins both healthy metabolism and oxidative stress related diseases.

氧化代谢的进化塑造了地球上的生命，从古老的厌氧微生物到现代的真核生物。有氧生命的核心是金属蛋白通过严格控制的生化过程调节和利用双氧的能力。从含氧光合作用和有氧呼吸的出现开始，重点介绍了金属酶在双氧激活、利用和解毒中的关键作用。从生物无机化学、酶学、合成生物学和微生物组学的角度，我们讨论了仿生分子复合物和天然和人工金属蛋白的研究如何阐明用于管理双氧反应性的结构和功能策略。我们进一步考虑了金属离子在维持氧化还原平衡，形成宿主-微生物相互作用以及在失调时导致病理结果中的系统作用。为理解金属离子在支撑健康代谢和氧化应激相关疾病的双氧化学中所起的关键作用奠定了基础。

引用次数: 0

The effect of ancillary ligands on vasodilatory activity of nitrosyl ruthenium complexes 辅助配体对亚硝基钌络合物血管扩张活性的影响。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-06 DOI: 10.1016/j.jinorgbio.2025.113144

Iury A. Paz , Carlos D.S. Silva , Edinilton M. Carvalho , Cássio S. Meira , Milena B.P. Soares , Izaura C.N. Diógenes , Nilberto R.F. Nascimento , Eduardo H.S. Sousa , Luiz G.F. Lopes

Sodium nitroprusside (Na₂[Fe(CN)₅NO], SNP) has long been administered in emergencies to reduce the blood pressure of cardiovascular patients. Despite resolution, NO rapid release and the toxicity of cyanide associated with SNP cause substantial harm. This study investigated three nitrosyl ruthenium complexes for vasodilatory activity, focusing on controlled NO release from a non-toxic compound. Cis-[Ru(bpy)₂(5-ain)NO](PF₆)₃ (5-ainBpy), cis-[Ru(phen)₂(5-ain)NO](PF₆)₃ (5-ainPhen), and cis-[Ru(phen)₂(SO₃)NO]PF₆ (SO₃Phen), where bpy = 2,2′-bipyridine, phen = 1,10-phenantroline, and 5-ain = 5-azaindole, were fully characterized by electrochemical and spectroscopic techniques, and showed no toxicity against rat cardiomyoblast (H9c2) and murine fibroblast cells (L929). Vasodilatory assays were conducted on pre-contracted rat thoracic aortic rings using SNP as reference compound. All complexes exhibited efficacies comparable to SNP (from 134 to 146 %), yet only SO₃Phen showed a 160-fold lower potency, suggesting that the ancillary ligand 5-azaindole exerts a stronger influence. Kinetic data showed that the maximum efficacy of the vasodilatory activity is reached by 5-ainBpy and 5-ainPhen after 15 and 23 min, respectively, while just 1 min is needed for SNP. For the sulfite complex, only 65 % of relaxation was achieved after 30 min. The results suggest that the vasodilatory activity of the studied complexes is associated with the easiness and rate of the NO release which, in turn, is strongly dependent on the chemical nature of the ancillary ligands occupying the cis position to NO. Current experiments with complexes containing ligands of varying π Lewis acid strength in the cis position to NO are being conducted to further validate the proposed hypothesis.

硝普钠（Na2[Fe(CN)5NO]， SNP）长期以来被用于急诊降低心血管患者的血压。尽管解决了，NO的快速释放和与SNP相关的氰化物毒性造成了实质性的危害。本研究考察了三种亚硝基钌配合物的血管舒张活性，重点研究了一种无毒化合物对NO释放的控制。通过电化学和光谱技术对顺式-[Ru(bpy)2(5-ain)NO](PF6)3 (5-ainBpy)，顺式-[Ru(phen)2(5-ain)NO](PF6)3 （5-ainPhen）和顺式-[Ru(phen)2(SO3)NO]PF6 （SO3Phen）进行了表征，其中bpy = 2,2'-联吡啶，phen = 1,10-菲安嘌呤，5-ain = 5-偶氮酚，对大鼠成心肌细胞（H9c2）和小鼠成纤维细胞（L929）无毒性。以SNP为参比化合物，对预收缩大鼠胸主动脉环进行血管舒张试验。所有复合物都显示出与SNP相当的效力（从134到146%），但只有SO3Phen的效力低160倍，这表明辅助配体5-吲哚具有更强的影响。动力学数据显示，5-ainBpy和5-ainPhen分别在15和23分钟后达到血管扩张活性的最大功效，而SNP只需要1分钟。对于亚硫酸盐络合物，30分钟后只有65%的弛豫实现。结果表明，所研究的复合物的血管扩张活性与NO释放的难易程度和速度有关，而NO释放的难易程度和速度又强烈依赖于占据NO顺式位置的辅助配体的化学性质。目前正在进行含有不同π路易斯酸强度的配体的配合物的实验，以进一步验证所提出的假设。

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引用次数: 0

Methionine coordination to the heme iron and its displacement by nitric oxide in the CcoP subunit of Pseudomonas aeruginosa cytochrome cbb3 oxidase 铜绿假单胞菌细胞色素cbb3氧化酶CcoP亚基中蛋氨酸与血红素铁的配位及其被一氧化氮取代

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-06 DOI: 10.1016/j.jinorgbio.2025.113146

Jia Yang , Fangfang Zhong , Therese Albert , Pierre Moënne-Loccoz , Ekaterina V. Pletneva

Ligand substitution is common in signaling mechanisms of heme proteins. Methionine at the heme iron can get displaced by both endogenous and exogeneous ligands, including NO. The latter is particularly relevant in low-O₂ environments and affects properties of metalloproteins in electron-transfer (ET) chains. Inspection of the recent cryo-EM structures of cytochrome (cyt) cbb₃ oxidases from Pseudomonas aeruginosa (Pa) suggested that FeS(Met) distances in the CcoP subunit are too long for Met ligation to the heme iron, yet this ligation is critical for high reduction potentials to support downhill ET to this terminal oxidase. Using spectroscopic and electrochemical characterization, we show that the two hemes of the CcoP subunit of Pa cbb₃–2 oxidase (CcoP2) are Met-ligated. Two variants of Pa CcoP2 were examined: wild-type (WT, referred here as IMA) and the I185A/A187P mutant (referred as AMP). Thermal denaturation and electrochemistry experiments show that the IMA to AMP substitution increases the protein global stability by ∼5 kcal/mol, in both ferric and ferrous forms. Molecular dynamics (MD) simulations suggest that mutational perturbations near the Met ligand propagate to interfacial loops of the two domains. As with horse heart cyt c, NO binds to ferric Pa CcoP2 proteins, but this binding is less thermodynamically favored, even less so in the AMP variant. MD simulations illustrate the preference for the swapped architecture in CcoP proteins and we propose functional advantages of this arrangement for ET proteins.

配体取代在血红素蛋白的信号机制中是常见的。血红素铁上的蛋氨酸可以被内源性和外源性配体取代，包括NO。后者在低氧环境中特别相关，并影响电子转移（ET）链中金属蛋白的性质。铜绿假单胞菌（Pa）细胞色素（cyt） cbb3氧化酶最近的低温电镜结构检查表明，CcoP亚基中的FeS（Met）距离太长，无法连接到血红素铁，但这种连接对于高还原电位支持下坡ET到末端氧化酶至关重要。通过光谱和电化学表征，我们发现Pa cbb3-2氧化酶（CcoP2）的两个亚基的两个血红素是met连接的。研究了Pa CcoP2的两种变体：野生型（WT，这里称为IMA）和I185A/A187P突变体（称为AMP）。热变性和电化学实验表明，在铁和亚铁形式下，IMA取代AMP使蛋白质的整体稳定性提高了约5 kcal/mol。分子动力学（MD）模拟表明，Met配体附近的突变扰动传播到两个结构域的界面环。与马心脏细胞c一样，NO与铁Pa CcoP2蛋白结合，但这种结合在热力学上不太受欢迎，在AMP变体中更不受欢迎。MD模拟显示了CcoP蛋白对交换结构的偏好，我们提出了这种排列对ET蛋白的功能优势。

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引用次数: 0

Copper(II) and zinc(II) complexes of dimeric 8-hydroxyquinoline ligands: Synthesis, metal speciation, and biological evaluation 二聚8-羟基喹啉配体的铜（II）和锌（II）配合物：合成、金属形态和生物学评价

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-04 DOI: 10.1016/j.jinorgbio.2025.113138

Roberta Panebianco , Giuseppina D.G. Santonoceta , Roberta Borrelli , Maria G.G. Pittalà , Rosaria Saletti , Carmelo Sgarlata , Maurizio Viale , Salvatore Furnari , Virginia Fuochi , Pio M. Furneri , Tommaso Mecca , Graziella Vecchio

Hydroxyquinolines have garnered considerable attention due to their biomedical potential, particularly their ability to coordinate metal ions, which significantly influences their biological activity.

In this study, a series of 8-hydroxyquinoline dimeric derivatives was synthesized and compared to their monomeric counterparts. The metal-binding properties of these compounds with zinc(II) and copper(II) ions were investigated using ESI-MS spectrometry and UV–Vis spectrophotometry. The results revealed that 8-hydroxyquinoline dimers form highly stable metal complexes.

Biological studies have demonstrated that the functionalization of the 8-hydroxyquinoline scaffold modulates its activity: the introduction of amine chains in monomeric systems decreases the antiproliferative effects, both in the ligands and their metal complexes. Notably, the dimer derivative linked via diaminoethane exhibited the most potent antiproliferative and antibacterial activities. In contrast, the introduction of a diaminodioxaoctane linker reduced toxicity in bacteria and cancer cells, highlighting its promise as a biologically compatible metal-chelating agent.

羟基喹啉类由于其生物医学潜力，特别是其配合金属离子的能力而引起了相当大的关注，这极大地影响了它们的生物活性。本研究合成了一系列8-羟基喹啉二聚体衍生物，并与它们的单体衍生物进行了比较。采用ESI-MS光谱法和UV-Vis分光光度法研究了这些化合物与锌（II）和铜（II）离子的金属结合性能。结果表明，8-羟基喹啉二聚体形成高度稳定的金属配合物。生物学研究表明，8-羟基喹啉支架的功能化调节了其活性：在单体系统中引入胺链降低了配体及其金属配合物的抗增殖作用。值得注意的是，二氨基乙烷连接的二聚体衍生物表现出最有效的抗增殖和抗菌活性。相比之下，二氨基二恶辛烷连接剂的引入降低了对细菌和癌细胞的毒性，突出了其作为生物相容性金属螯合剂的前景。

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引用次数: 0

Synthesis, structure, and anticancer activity of Ni(II) complexes derived from polyhalogenated 2-aminophenol Schiff bases 多卤化2-氨基酚席夫碱衍生的Ni（II）配合物的合成、结构和抗癌活性

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-04 DOI: 10.1016/j.jinorgbio.2025.113139

Houcong Li , Huijuan Li , Mingzhu Wang , Yefan Zheng , Wenge Li , Jing Hu

Six Schiff bases (H₂L1-H₂L6) were synthesized by the reaction of 3,5-substituted salicylaldehyde (F/Cl/Br) with 2-amino-4-substituted phenol (F/Cl/Br), and their Ni(II) complexes (C1-C6) were obtained with NiCl₂·6H₂O, respectively. All complexes were characterized via infrared spectroscopy, NMR spectra analysis, UV–visible spectroscopy, thermal stability analysis, elemental analysis, X-ray powder diffraction, single-crystal X-ray diffraction, ICP-OES analysis, and lipophilicity assay. Single crystal X-ray analysis reveals that complexes C1, C4, C5, and C6 crystallize in a monoclinic system with space group I4₁/a, while complexes C2 and C3 crystallize in the trigonal system with space group P-1. The cytotoxicity of polyhalogenated 2-amino-phenol Schiff base ligands and their metal complexes on breast cancer cells (SKBR3), nasopharyngeal carcinoma cells (CNE-2Z), lung cancer cells (A549), rectal cancer cells (HCT-116) and two types of normal human cells (IOSE 80 and MCF-10 A) was determined by MTT assay. The results showed that C1-C6 complexes exhibited stronger anticancer efficacy on SKBR3 cells than ligands and cisplatin. Among them, C5, C6 and C4 could increase intracellular reactive oxygen species levels, reduce the mitochondrial membrane potential, arrest cells in the G0/G1 phase, induce SKBR3 cell apoptosis in a dose-dependent manner and promote Bax protein expression and inhibit Bcl-2 protein expression in vitro experiments. In vivo experiments showed that the C5 complex significantly suppressed SKBR3 tumor growth with low toxicity to major organs in the nude mice model.

以3,5取代水杨醛（F/Cl/Br）和2-氨基-4取代苯酚（F/Cl/Br）为原料合成了6个席夫碱（H₂l1 ~ H₂L6），并分别与NiCl₂·6H₂O反应得到了它们的Ni（II）配合物（c1 ~ c6）。通过红外光谱分析、核磁共振光谱分析、紫外可见光谱分析、热稳定性分析、元素分析、x射线粉末衍射、单晶x射线衍射、ICP-OES分析和亲脂性分析对所有配合物进行了表征。单晶x射线分析表明，配合物C1、C4、C5和C6在单斜晶系中结晶，空间群为I41/a；配合物C2和C3在三角形晶系中结晶，空间群为P-1。采用MTT法测定了多卤化2-氨基酚希夫碱配体及其金属配合物对乳腺癌细胞（SKBR3）、鼻咽癌细胞（CNE-2Z）、肺癌细胞（A549）、直肠癌细胞（HCT-116）和两种正常人细胞（IOSE 80和mcf - 10a）的细胞毒性。结果表明，C1-C6复合物对SKBR3细胞的抗癌作用强于配体和顺铂。其中C5、C6、C4在体外实验中可增加细胞内活性氧水平，降低线粒体膜电位，使细胞停留在G0/G1期，呈剂量依赖性诱导SKBR3细胞凋亡，促进Bax蛋白表达，抑制Bcl-2蛋白表达。体内实验表明，C5复合物在裸鼠模型中显著抑制SKBR3肿瘤生长，且对主要器官毒性低。

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引用次数: 0