Journal of Inorganic Biochemistry最新文献_第2页

Targeting non-canonical DNA with π-extended Schiff Base complexes of Zinc(II), Copper(II), and Nickel(II): Insights into G-Quadruplex binding modes 锌（II）、铜（II）和镍（II）的π扩展希夫碱配合物靶向非典型DNA: g -四重体结合模式的研究

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-30 DOI: 10.1016/j.jinorgbio.2025.113160

Luisa D'Anna, Silvia Lo Iacono, Laura Marretta, Simona Rubino, Antonio Palumbo Piccionello, Riccardo Bonsignore, Giampaolo Barone

The selective recognition of G-quadruplex (G4) DNA structures by metal complexes holds considerable promise for anticancer drug development, particularly for targeting oncogene promoters and telomeric regions. Herein, we report the synthesis, structural characterization, and DNA-binding strength evaluation of a new series of transition metal complexes derived from a N₄ tetradentate naphthalene-bridged Schiff base ligand (Naphthim). The zinc(II), copper(II) and nickel(II) complexes were obtained via in situ or transmetallation protocols and characterized by NMR, HR-ESI-MS, and elemental analysis. Among them, the copper(II) complex, 2, [CuNaphthim]²⁺, exhibited the highest DNA-binding affinity and G4-stabilizing ability, as assessed by FRET-based DNA melting assays, UV–Vis absorption, and circular dichroism (CD) spectroscopy. Despite lacking cationic side chain substituents, 2 showed moderate stabilization of several G4 structures, with a preferential effect on the cMyc quadruplex. Comparative studies with the benchmark [CuPhenim]²⁺ complex revealed that π-extension of the ligand framework substantially enhances DNA-binding affinity and modulates selectivity.

UV–Vis and CD spectroscopy revealed clear differences in DNA-binding behavior between 2 and [CuPhenim]²⁺, with compound 2 exhibiting stronger and more defined interactions across both G4 and duplex targets. These trends found support by molecular docking, which uncovered distinct binding modes depending on G4 topology and echoed the observed affinity profiles. These findings highlight the Naphthim scaffold as a promising modular platform for the design of G4-targeting metal complexes.

金属配合物对g -四重体（G4） DNA结构的选择性识别为抗癌药物的开发提供了可观的前景，特别是针对癌基因启动子和端粒区域。在此，我们报道了一系列新的过渡金属配合物的合成、结构表征和dna结合强度评价，这些配合物是由N4四齿萘桥接席夫碱配体（Naphthim）衍生的。锌（II）、铜（II）和镍（II）配合物通过原位或金属转化获得，并通过NMR、HR-ESI-MS和元素分析进行了表征。其中，铜（II）配合物2，[CuNaphthim]2+，表现出最高的DNA结合亲和力和g4稳定能力，通过基于fret的DNA熔化试验，紫外-可见吸收和圆二色性（CD）光谱进行了评估。尽管缺乏阳离子侧链取代基，2对几种G4结构表现出适度的稳定，对cMyc四联体有优先作用。与基准的[CuPhenim]2+配合物的比较研究表明，配体框架的π扩展可显著增强dna结合亲和力并调节选择性。紫外-可见光谱和CD光谱显示了2和[CuPhenim]2+之间dna结合行为的明显差异，化合物2在G4和双工靶标上表现出更强、更明确的相互作用。这些趋势得到了分子对接的支持，分子对接揭示了依赖于G4拓扑结构的不同结合模式，并与观察到的亲和谱相呼应。这些发现突出了萘啶支架作为设计g4靶向金属配合物的有前途的模块化平台。

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引用次数: 0

Potent anticancer 5-fluorouracil platinum(IV) prodrugs 强效抗癌5-氟尿嘧啶铂（IV）前药。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-27 DOI: 10.1016/j.jinorgbio.2025.113165

Aleen Khoury , Maria George Elias , Jennette A. Sakoff , Jayne Gilbert , Kieran F. Scott , Janice R. Aldrich-Wright

Six platinum(IV) prodrugs incorporating 5-fluorouracil (5FU) derivatives in the axial positions were synthesised, purified, fully characterised, and their biological activity assessed. The 5FU derivatives, 5FU-acetate and 5FU-methoxybutanoate, were successfully coordinated to [Pt(P_L)(1S,2S-diaminocyclohexane)(OH)₂]²⁺ scaffolds, where P_L = 1,10-phenanthroline (Phen) or 5,6-dimethyl-1,10-phenanthroline (56Me₂Phen). All complexes exhibited exceptional in vitro cytotoxicity across a broad panel of cancer cell lines, with [Pt^IV(56Me₂Phen)(1S,2S-diaminocyclohexane)(5FU-methoxybutanoate)(OH)](NO₃)₂ (6) demonstrating the lowest GI₅₀ of 1 nM against the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 6 being up to 1400-fold more active in selected cancer cell lines. Complexes incorporating the 5FU-methoxybutanoate ligand (5 and 6) were notably more cytotoxic and lipophilic than their 5FU-acetate analogues (1–3), with 6 also exhibiting ∼2-fold greater potency than its platinum(II) precursor. Further studies in the HT29 colon cancer cell line revealed that 5 and 6 induced sustained elevations in reactive oxygen species (ROS) and substantial reductions in mitochondrial membrane potential, indicating that oxidative stress and mitochondrial dysfunction contributed to their cytotoxicity. Collectively, these findings demonstrate that the incorporation of 5FU into platinum(IV) prodrugs enhances both potency and mechanistic activity, with prodrug 6 emerging as a highly promising anticancer candidate.

合成了6种轴位含有5-氟尿嘧啶（5FU）衍生物的铂（IV）前药，对其进行了纯化、完全表征并评估了其生物活性。5FU衍生物5FU-乙酸酯和5FU-甲氧基丁酸酯成功地配位到[Pt(PL)（1S， 2s -二氨基环己烷）（OH） 2]2+支架上，其中PL = 1,10-菲罗啉（Phen）或5,6-二甲基-1,10-菲罗啉（56Me₂Phen）。所有配合物在广泛的癌细胞系中都表现出异常的体外细胞毒性，其中[PtIV(56Me2Phen)（1S， 2s -二氨基环己烷）（5fu -甲氧基丁酸盐）（OH）](NO3)2(6)对前列腺Du145癌细胞系显示出最低的GI₅0为1 nM。与顺铂相比，每种复合物都显示出显著增强的活性，其中6种在选定的癌细胞系中活性高达1400倍。含有5fu -甲氧基丁酸配体（5和6）的配合物明显比它们的5fu -乙酸类似物更具有细胞毒性和亲脂性（1-3），其中6也表现出比其铂（II）前体高2倍的效力。对HT29结肠癌细胞系的进一步研究表明，5和6诱导活性氧（ROS）持续升高，线粒体膜电位大幅降低，表明氧化应激和线粒体功能障碍与它们的细胞毒性有关。总之，这些发现表明5FU与铂（IV）前药的结合增强了效力和机制活性，前药6成为一种非常有前途的抗癌候选药物。

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引用次数: 0

Rare examples of rhenium(I) tricarbonyl iodido complexes with unsymmetrical bipyridines featuring distinguishable rotamers: From synthesis and solid-state/solution-phase isomerism to biological activity 具有可区分旋转体的不对称联吡啶的三羰基碘铼配合物的罕见例子：从合成和固/溶相异构到生物活性。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-27 DOI: 10.1016/j.jinorgbio.2025.113167

Enis Šuta , Adnan Zahirović , Vele Tešević , Sanja Grgurić-Šipka , Sandra Aranđelović , Sead Ljubijankić , Jovana Ljujić , Milica Balaban , Armin Hrnjić , Aleksandar Višnjevac , Nevzeta Ljubijankić

Three novel unsymmetrically substituted 2,2′-bipyridine ligands were prepared by introducing a 2-hydroxyphenyl group at the 6-position and either a 4-methoxyphenyl, 3,4-dimethoxyphenyl or 3,4-methylenedioxyphenyl group at the 4-position, using a modified Kröhnke protocol. Their corresponding rhenium(I) tricarbonyl iodido complexes, fac-[Re(L)(CO)₃I], 1–3, were synthesized and comprehensively characterized by single-crystal X-ray diffraction (SCXRD), ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, ultraviolet–visible (UV–Vis) spectroscopy, cyclic voltammetry (CV), high-resolution mass spectrometry (HRMS), and elemental analysis. The common 6-(2-hydroxyphenyl) moiety predominantly influences the spectroscopic and redox properties of the complexes. SCXRD confirms the facial arrangement of the fac-[Re(CO)₃N₂I] core in all three cases, although solid-state conformational isomerism was observed only in complex 1. In contrast, two NMR-distinguishable isomers are observed in solution for all three complexes. The cytotoxicity of 1–3 was evaluated by MTT assay after 48 h of continuous exposure in several human tumor cell lines (HeLa, PANC-1, MDA-MB-231, A549) and in non-malignant human lung fibroblasts (MRC-5). Notably, all three complexes displayed low-micromolar IC₅₀ values comparable to cisplatin, with the highest activity observed in HeLa cells (5.11–7.45 μM). However, significant activity was also recorded in MRC-5 cells (IC₅₀ = 8.19–8.95 μM), suggesting higher overall toxicity and weaker selectivity compared to cisplatin. Analysis in HeLa cells using bright-field microscopy confirmed a substantial antiproliferative effect.

采用改进的Kröhnke方法，在6位上引入2-羟基苯基，在4位上引入4-甲氧基苯基、3,4-二甲氧基苯基或3,4-亚二氧基苯基，制备了3种新的不对称取代2,2'-联吡啶配体。合成了相应的铼(I)三羰基碘配合物fac-[Re(L)(CO)3I], 1-3，并通过单晶x射线衍射（SCXRD）、1H和13C核磁共振（NMR）光谱、红外（IR）光谱、紫外-可见（UV-Vis）光谱、循环伏安（CV）、高分辨率质谱（HRMS）和元素分析对其进行了综合表征。常见的6-（2-羟基苯基）片段主要影响配合物的光谱和氧化还原性质。SCXRD证实了这三种情况下的face -[Re(CO)3N2I]核的面向排列，尽管只有在配合物1中观察到固态构象异构。相比之下，两个核磁共振可区分异构体在溶液中观察到所有三个配合物。在连续暴露于几种人肿瘤细胞系（HeLa、PANC-1、MDA-MB-231、A549）和非恶性人肺成纤维细胞（MRC-5） 48小时后，用MTT法评估1-3的细胞毒性。值得注意的是，这三种配合物的IC50值与顺铂相当，在HeLa细胞（5.11-7.45 μM）中活性最高。然而，在MRC-5细胞中也记录了显著的活性（IC50 = 8.19-8.95 μM），表明与顺铂相比，总毒性更高，选择性更弱。在HeLa细胞中使用明场显微镜分析证实了其显著的抗增殖作用。

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引用次数: 0

An electrochemical perspective on human sulfite oxidase as a potential nitrite reductase 人亚硫酸盐氧化酶作为潜在亚硝酸盐还原酶的电化学研究。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-26 DOI: 10.1016/j.jinorgbio.2025.113159

Peter D. Giang , Joan Zapiter , Jiayun Zhou , Alexander T. Kaczmarek , Günter Schwarz , Paul V. Bernhardt

The Mo-dependent enzyme human sulfite oxidase (HSO) oxidises highly neurotoxic sulfite to benign sulfate in the final step of cysteine catabolism. Although sulfite is its only known physiological substrate, HSO has been suggested to play a role in the generation of nitric oxide (NO) from nitrite under ischemic conditions. In this work we have investigated the electrochemically driven nitrite reductase activity of HSO mediated by the benzyl viologen radical cation. We show that HSO can act as an effective nitrite reductase with a K_M value of 3.5 mM at pH 7. A heme-free variant of HSO behaves similarly. We also demonstrate electrochemically driven tandem sulfite oxidation and nitrite reduction with HSO using a known Fe^III coordination compound as mediator. Significant pH-dependence of catalytic activity is found.

在半胱氨酸分解代谢的最后一步，钼依赖酶人亚硫酸盐氧化酶（HSO）将高度神经毒性亚硫酸盐氧化为良性硫酸盐。虽然亚硫酸盐是其唯一已知的生理底物，但HSO已被认为在缺血条件下亚硝酸盐生成一氧化氮（NO）中发挥作用。在这项工作中，我们研究了电化学驱动的亚硝酸盐还原酶活性的HSO介导的苯紫根自由基阳离子。结果表明，在pH为7时，HSO可以作为一种有效的亚硝酸盐还原酶，KM值为3.5 mM。HSO的无血红素变体也有类似的行为。我们也证明了电化学驱动串联亚硝酸盐氧化和亚硝酸盐还原与HSO使用已知的FeIII配位化合物作为介质。发现催化活性显著的ph依赖性。

引用次数: 0

A new interpretation for oxygen atom-transfer reactions for the Berg-Holm Oxomolybdenum enzyme model: Evidence for a highly active oxygen atom transfer acceptor Berg-Holm氧钼酶模型对氧原子转移反应的新解释：一个高活性氧原子转移受体的证据。

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-25 DOI: 10.1016/j.jinorgbio.2025.113163

Jeremy M. Berg

In 1984, a synthetic model system for certain molybdenum oxotransferase enzymes was reported. These reports claimed that an oxygen atom could be extracted from a designed dioxomolybdenum(VI) complex to produce a monoxomolybdenum(IV) complex without the formation of an oxo-bridged molybdenum(V) binuclear species. The reduced product was shown to accept oxygen atoms from substrates such as dimethylsulfoxide with substrate saturation kinetics. Fifteen years later, it was demonstrated that the reduced product was, in fact, the oxo-bridged molybdenum(V) binuclear species. Here, it is shown that the kinetic data can be reinterpreted in terms of rate-limiting disproportionation of the oxo-bridged molybdenum(V) binuclear species to form a highly reactive monoxomolybdenum(IV) complex. The second order rate constant for oxygen atom transfer from dimethyl sulfoxide to this complex is more than 100,000 times higher than those reported for other monoxomolybdenum(IV) complexes. The five-coordinate molybdenum sites in the dioxomolybdenum(VI) and presumed monoxomolybdenum(IV) complexes are quite similar to those observed for eukaryotic nitrate reductase enzymes and this model system shows relatively rapid reduction of nitrate through a similar mechanistic scheme.

1984年，报道了某些钼氧转移酶的合成模型体系。这些报告声称，可以从设计的二氧钼（VI）配合物中提取一个氧原子，生成单氧钼（IV）配合物，而不会形成氧桥接的钼(V)双核物质。还原产物被证明可以接受来自底物如二甲基亚砜的氧原子，具有底物饱和动力学。15年后，证明了还原产物实际上是氧桥式钼(V)双核物质。本文表明，动力学数据可以用氧桥接钼(V)双核物种的限速歧化来重新解释，以形成高活性的单氧钼（IV）配合物。氧原子从二甲基亚砜转移到该配合物的二级速率常数比其他单钼（IV）配合物高10万倍以上。二氧钼（VI）和假定的单氧钼（IV）配合物中的五坐标钼位点与真核硝酸还原酶中观察到的非常相似，该模型系统通过类似的机制方案显示出相对快速的硝酸还原。

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引用次数: 0

The Neisseria gonorrhoeae cytochrome c2-bacterial peroxidase electron-transfer complex is competent in hydrogen peroxide reduction 淋病奈瑟菌细胞色素c2-细菌过氧化物酶电子转移复合物在过氧化氢还原中是有效的

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-25 DOI: 10.1016/j.jinorgbio.2025.113164

Pedro M.S. Bragança , Daniela S. Barreiro , Marta S.P. Carepo , Sofia R. Pauleta

Neisseria gonorrhoeae is a pathogenic bacterium responsible for the disease gonorrhea, which has gained increasing attention in recent years due to the emergence of strains resistant to the currently used antibiotics. In the absence of a vaccine, understanding mechanisms that contribute to infection is imperative. One such mechanism is the reduction of hydrogen peroxide by the outer membrane bound bacterial peroxidase. Here, steady-state kinetics shows that cytochrome c₂, previously implicated in nitrite reduction, is an efficient electron donor to this enzyme, proving to be an alternative to the lipid-modified azurin. The cytochrome c₂-mediated peroxidase activity has a K_M of 0.74 ± 0.08 μM and a k_obs of 18 ± 1 s⁻¹ for hydrogen peroxide, with an optimum pH at 7.7. The pH and ionic-strength dependence of this activity differs from that of azurin, suggesting that the two electron donors can play complementary roles depending on external conditions. Furthermore, the viscosity dependence of the activity suggests that protein-protein interactions are not purely diffusion-controlled but also governed by conformational changes required for complex formation and/or electron transfer, and docking analysis implies that cytochrome c₂ binds near the exposed edge of the electron transferring heme of the bacterial peroxidase.

This study improves our understanding of the periplasmic physiology of N. gonorrhoeae by demonstrating how the pathogen's flexibility in using electron donors enables it to maintain peroxidase activity and cope with oxidative stress in different host environments. These insights could inform future strategies aimed at disrupting redox homeostasis to combat antibiotic-resistant strains.

淋病奈瑟菌是一种导致淋病的致病菌，近年来由于出现了对目前使用的抗生素具有耐药性的菌株，淋病奈瑟菌越来越受到关注。在没有疫苗的情况下，了解导致感染的机制至关重要。其中一种机制是外膜结合细菌过氧化物酶对过氧化氢的还原。这里，稳态动力学表明，细胞色素c2，先前涉及亚硝酸盐还原，是该酶的有效电子供体，证明是脂质修饰的azurin的替代品。过氧化氢介导的细胞色素c2过氧化物酶活性KM为0.74±0.08 μM， kobs为18±1 s−1，最适pH为7.7。该活性对pH值和离子强度的依赖性与azurin不同，这表明两个电子给体可以根据外部条件发挥互补作用。此外，活性的黏度依赖性表明，蛋白质-蛋白质相互作用不是纯粹由扩散控制的，而是由复合体形成和/或电子转移所需的构象变化控制的，对接分析表明，细胞色素c2结合在细菌过氧化物酶的电子转移血红素的暴露边缘附近。本研究通过展示淋病奈瑟菌在使用电子供体方面的灵活性如何使其在不同宿主环境中维持过氧化物酶活性并应对氧化应激，提高了我们对淋病奈瑟菌质周生理学的理解。这些见解可以为未来旨在破坏氧化还原稳态以对抗抗生素耐药菌株的策略提供信息。

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引用次数: 0

Impact of electrostatic distribution in CYP3A4 on the regioselectivity of triazolam metabolism and regulation of its metabolic rate by the iron spin states: Insights from MD simulations and QM calculations CYP3A4静电分布对三唑仑代谢区域选择性的影响以及铁自旋态对其代谢速率的调节：来自MD模拟和QM计算的见解

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-25 DOI: 10.1016/j.jinorgbio.2025.113162

Yan Zhao , Xinyu Ma , Qingchuan Zheng

Triazolam (TRZ) is a representative benzodiazepine sedative-hypnotic drug that has gradually been abused due to the increasing societal pressures. To further provide a theoretical basis for the rationale use of TRZ and obtain more information for its metabolic process, in this study, human CYP3A4 was employed as the metabolic enzyme to investigate the metabolic mechanism of TRZ by multiple computational methods. Here, three types of substrate-binding conformations related to the diversity of TRZ metabolites are identified (pose A, pose B and pose C). The “sandwich” structure and the π-π stacking between TRZ and F304/porphyrin ring may be the key factors in dominating three substrate-binding conformations. Furthermore, we discovered pose A is the predominant binding mode, with Cα-H serving as the key metabolic site and CYP3A4-catalyzed Cα-H hydroxylation follows a hydrogen abstraction-rebound mechanism. More importantly, in hydroxylation process, the spin states of iron can regulate the metabolic reaction rate of TRZ and the highest rate of metabolism (5.96 s⁻¹) is found in the quartet spin states. Based on our findings, it can be suggested that rational incorporating aromatic groups into TRZ could improve its metabolic stability. Meanwhile, the transition of the heme iron from a low-spin to a high-spin state appears to accelerate TRZ metabolism, potentially leading to the accumulation of α-OH triazolam in vivo, which may pose risks to human health. These results could enhance our understanding of CYP3A4-mediated regioselective metabolism of TRZ and provide a theoretical foundation and new perspective for studies on the metabolism of other triazole drugs.

三唑仑（TRZ）是一种典型的苯二氮卓类镇静催眠药物，由于社会压力的增加而逐渐被滥用。为了进一步为TRZ的合理使用提供理论依据，获得更多关于其代谢过程的信息，本研究以人CYP3A4为代谢酶，通过多种计算方法研究TRZ的代谢机制。在这里，确定了三种与TRZ代谢物多样性相关的底物结合构象（pose A， pose B和pose C）。TRZ和F304/卟啉环之间的“三明治”结构和π-π堆积可能是决定三种底物结合构象的关键因素。此外，我们发现姿势A是主要的结合模式，Cα-H是关键的代谢位点，cyp3a4催化的Cα-H羟基化遵循氢提取-反弹机制。更重要的是，在羟基化过程中，铁的自旋态可以调节TRZ的代谢反应速率，其中四重奏自旋态的代谢速率最高（5.96 s−1）。综上所述，在TRZ中合理掺入芳香族可以提高其代谢稳定性。同时，血红素铁从低自旋到高自旋状态的转变似乎加速了TRZ的代谢，可能导致α-OH三唑仑在体内蓄积，可能对人体健康造成危害。这些结果可以加深我们对cyp3a4介导的TRZ的区域选择性代谢的认识，并为其他三唑类药物的代谢研究提供理论基础和新的视角。

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引用次数: 0

Thiodiacetate vs. oxydiacetate: physicochemical and biological properties of new heteroligand (acetylacetonate)oxidovanadium(IV) complexes 硫代二乙酸酯与氧化二乙酸酯：新型异聚物（乙酰丙酮酸）氧化钒（IV）配合物的理化和生物学特性

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-24 DOI: 10.1016/j.jinorgbio.2025.113155

Dariusz Wyrzykowski , Katarzyna Chmur , Jakub Brzeski , Artur Sikorski , Olga Tovchiga , Justyna Budka , Iwona Inkielewicz-Stępniak , Aleksandra Tesmar

This research aimed to compare the crystal structure, physicochemical, and biological properties of novel (acetylacetonate)(thiodiacetato)oxidovanadium(IV) complex salts, namely [QH][VO(acac)(tda)] (1) and [(acr)H][VO(acac)(tda)] (2) (acac = acetylacetonate, tda²⁻ = thiodiacetate, Q = quinoline, acr = acridine) with previously reported oxydiacetate (oda⁻) analogues: [QH][VO(acac)(oda)] (3) and [(acr)H][VO(acac)(oda)](H₂O)₂ (4). A combination of experimental data, including X-ray crystallography, IR spectroscopy, potentiometric measurements and ESI-MS, and density functional theory (DFT) calculations enables thorough characterization of the complexes in the solid state and in solution. It has been demonstrated that the observed differences in the nature of VS (thioether) and VO (ether) dative bonds have only a slight impact on orbital energy levels and spin density distribution. At the same time, these minor differences do not significantly affect the thermodynamic stability of the complexes: logß₁₁₁₀ {[VO(acac)(tda)]⁻} = 16.91 and logß₁₁₁₀ {[VO(acac)(oda)]⁻} = 16.45. Additionally, the calculated thermodynamic parameters for the formation of these complexes (∆H, T∆S, ∆G in kcal mol⁻¹, at 298 K) are −66.72, −16.38, and − 50.34 for [VO(acac)(tda)]⁻, and − 68.47, −15.64, and − 52.82 for [VO(acac)(oda)]⁻, respectively. The biological evaluations showed promising selective cytotoxic activity of the investigated complex salts against the human osteosarcoma cell line MG-63. The mechanism of biological action of these complexes appears to involve disruption of cell cycle regulation and induction of apoptosis. The counterions (acridine and quinoline) alone do not significantly affect cell cycle distribution, suggesting that the cytotoxic and cell cycle effects are primarily due to the [VO(acac)(tda)]⁻ and [VO(acac)(oda)]⁻ species.

本研究旨在比较新型（乙酰丙酮）（硫代二乙酰乙酸）氧化钒（IV）络合盐[QH][VO(acac)(tda)](1)和[(acr)H][VO(acac)(tda)] (2) （acac =乙酰丙酮，tda2−=硫代二乙酸，Q =喹啉，acr =吖啶）与先前报道的氧化二乙酸（oda−）类似物[QH][VO(acac)(oda)](3)和[(acr)H][VO(acac)(oda)](H2O)2(4)的晶体结构、物理化学和生物学特性。结合实验数据，包括x射线晶体学、红外光谱、电位测量和ESI-MS，以及密度泛函理论（DFT）计算，可以全面表征固态和溶液中的配合物。已经证明，观察到的VS（硫醚）和VO（醚）键性质的差异对轨道能级和自旋密度分布只有轻微的影响。同时，这些微小的差异并没有显著影响配合物的热力学稳定性：logß1110 {[VO(acac)(tda)]−}= 16.91和logß1110 {[VO(acac)(oda)]−}= 16.45。此外，这些配合物形成的计算热力学参数（∆H,∆S,∆G, kcal mol−1，在298 K下）[VO(acac)(tda)]−分别为- 66.72,- 16.38和- 50.34,[VO(acac)(oda)]−分别为- 68.47,- 15.64和- 52.82。生物学评价表明，复合盐对MG-63人骨肉瘤细胞系具有良好的选择性细胞毒活性。这些复合物的生物作用机制似乎涉及破坏细胞周期调节和诱导细胞凋亡。单独的反离子（吖啶和喹啉）不会显著影响细胞周期分布，这表明细胞毒性和细胞周期效应主要是由[VO(acac)(tda)] -和[VO(acac)(oda)] -两种物质引起的。

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引用次数: 0

Three cobalt(II) complexes containing pyrimidylanthrahydrazone ligands: Synthesis, crystal structure, DNA binding, anticancer activity and structure-activity relationship 三种含嘧啶酰腙配体的钴（II）配合物：合成、晶体结构、DNA结合、抗癌活性及构效关系

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-24 DOI: 10.1016/j.jinorgbio.2025.113158

Jia-yu Xu , Xue-bin Bi , Sha-sha Luo, Yue Huang, Chen-yu Wang, Chang-chun Wen, Rui-xue Liu, Yan-cheng Liu, Hong Liang

This research presents the design, synthesis, structural characterization, and evaluation of the anticancer activities of three new pyrimidylanthrahydrazone cobalt(II) complexes: 1) 9-MPMAH-Co, 2) 9-FPMAH-Co, and 3) 9-PMAH-Co. Single-crystal X-ray diffraction analysis confirmed that all three complexes adopt a hexacoordinate mononuclear geometry. However, differences in their coordination modes were observed due to variations in the ligand substituents (-CH₃, -F, -H). Spectroscopic DNA interaction studies indicated that all three cobalt complexes exhibit varying levels of DNA intercalation. Topoisomerase I inhibition assays revealed that 9-PMAH-Co demonstrates significant enzyme inhibition at a low concentration of 1 μM. In vitro antiproliferative assays confirmed that 9-PMAH-Co exhibits potent cytotoxic activity against SK-OV-3 and HeLa-229 cancer cell lines, with IC₅₀ values of 4.99 ± 0.18 μM and 8.09 ± 1.13 μM, respectively, while showing reduced toxicity toward normal liver cells (HL-7702) compared to cisplatin. Further investigation through cell cycle analysis indicated that 9-PMAH-Co induces G2/M phase arrest in SK-OV-3 cells, with a population increase to 91.37 % (Δ = 76.59 %). Studies on the structural-activity relationship suggest that the synergistic interactions between the ligand substituents and the cobalt center play a crucial role in modulating biological activity, highlighting 9-PMAH-Co as a promising lead compound for the development of targeted anticancer agents.

本文介绍了三种新型嘧啶酰腙钴（II）配合物的设计、合成、结构表征和抗癌活性评价：1)9-MPMAH-Co、2)9-FPMAH-Co和3)9-PMAH-Co。单晶x射线衍射分析证实，这三种配合物均采用六坐标单核几何结构。然而，由于配体取代基（-CH3, -F, -H）的不同，它们的配位模式也不同。光谱DNA相互作用研究表明，这三种钴配合物都表现出不同水平的DNA嵌入。拓扑异构酶I抑制实验表明，在1 μM的低浓度下，9-PMAH-Co具有显著的酶抑制作用。体外抗增殖试验证实，9-PMAH-Co对SK-OV-3和HeLa-229癌细胞系具有强效的细胞毒活性，IC₅0值分别为4.99±0.18 μM和8.09±1.13 μM，与顺铂相比，对正常肝细胞（HL-7702）的毒性降低。进一步的细胞周期分析表明，9-PMAH-Co诱导SK-OV-3细胞G2/M期阻滞，种群增加到91.37% （Δ = 76.59%）。结构-活性关系的研究表明，配体取代基与钴中心之间的协同相互作用在调节生物活性中起着至关重要的作用，突出了9-PMAH-Co是开发靶向抗癌药物的有前途的先导化合物。

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引用次数: 0

Combined computational and bioinformatic approach to uncover the pre-covalent protein interactions of auranofin and its chlorido derivative Au(PEt₃)Cl 结合计算和生物信息学方法揭示金糠蛋白及其氯基衍生物Au（PEt₃）Cl的预共价蛋白相互作用

IF 3.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry

Pub Date : 2025-11-24 DOI: 10.1016/j.jinorgbio.2025.113161

Iogann Tolbatov , Alessandro Marrone

Auranofin (AF) is a clinically approved gold(I) metallodrug with recognized anti-inflammatory and anticancer properties, whose mechanism of action relies on the covalent binding at key selenoproteins and thiols causing their irreversible deactivation. While the final covalent binding event is well-documented, the initial non-covalent recognition phase that precedes it, and which likely governs the drug's selectivity, remains poorly characterized by experimental methods. To address this gap, we employed density functional theory (DFT) calculations to systematically investigate the weak, pre-covalent interactions between auranofin (AF) or its chlorido derivative, Au(PEt₃ )Cl (AFCl), with model protein residues. Our results reveal distinct non-covalent interactions preferences for each drug: AF shows a stronger affinity for charged amino acid residues, while AFCl exhibits a marked preference for aromatic and some charged residues. We demonstrate that these initial non-covalent interactions induce a significant redistribution of electron density. This effect alters the local electronic properties of the gold center and its bond to the labile ligand, effectively priming the drug for subsequent covalent attack. We then utilized the computationally derived geometric assets to perform a comprehensive motif search within the Protein Data Bank (PDB) database, which identified ten protein targets with significant therapeutic relevance. This bioinformatic analysis provided a general picture of how these gold compounds navigate their biological environment and led to the identification of targets. This pre-covalent interaction with protein is not a random anchoring process but a crucial preparatory step for the targeted attachment of gold-based drugs.

金嘌呤（AF）是一种临床批准的金(I)金属药物，具有公认的抗炎和抗癌特性，其作用机制依赖于关键硒蛋白和硫醇的共价结合，导致其不可逆失活。虽然最终的共价结合事件有充分的文献记载，但在此之前的初始非共价识别阶段，可能决定药物的选择性，仍然缺乏实验方法的表征。为了解决这一差距，我们采用密度泛函理论（DFT）计算系统地研究了金糠蛋白（AF）或其氯基衍生物Au(PEt3)Cl （AFCl）与模型蛋白残基之间的弱共价前相互作用。我们的研究结果揭示了每种药物不同的非共价相互作用偏好：AF对带电氨基酸残基表现出更强的亲和力，而AFCl对芳香和一些带电残基表现出明显的偏好。我们证明了这些初始的非共价相互作用诱导了电子密度的显著重新分布。这种效应改变了金中心的局部电子性质及其与不稳定配体的结合，有效地为随后的共价攻击准备了药物。然后，我们利用计算得出的几何资产在蛋白质数据库（PDB）数据库中进行全面的基序搜索，确定了10个具有显著治疗相关性的蛋白质靶点。这种生物信息学分析提供了这些金化合物如何导航其生物环境并导致目标识别的总体情况。这种与蛋白质的共价前相互作用不是一个随机的锚定过程，而是金基药物靶向附着的关键准备步骤。

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引用次数: 0