Pub Date : 2026-05-01Epub Date: 2026-01-31DOI: 10.1016/j.jinorgbio.2026.113247
Yu-Yi Ling , Liang Hao , Chunping Liao , Yujun He , Yinting Hu , Zitong Peng , Zhiyi Li , Lanmei Chen , Yongcun Wang , Jincan Chen
DNA damage is a critical approach in cancer therapy, and the regulation of the cell cycle to inhibit cell proliferation has become an important therapeutic strategy. In this study, two ruthenium(II) complexes, [Ru(phen)₂(1-(p-tolyl)-9H-pyrido[3,4-b]indole)]PF₆ (Ru1) and [Ru(phen)₂(1-(4-chlorophenyl)-9H-pyrido[3,4-b]indole)]PF₆ (Ru2), featuring β-carboline as the primary ligand, were designed and synthesized. The results demonstrated that both Ru1 and Ru2 exhibit significant antitumor activity in vitro. These complexes can bind to DNA in the cell nucleus, induce DNA damage through reactive oxygen species (ROS) generation, and cause S-phase cell cycle arrest. Furthermore, Ru1 effectively triggers autophagy in tumor cells. Ultimately, these mechanisms collectively lead to apoptosis. In summary, we report a DNA-targeting ruthenium complex capable of efficiently inducing DNA damage, promoting autophagy and apoptosis in tumor cells, thereby exerting potent antitumor effects. This work provides a novel strategy for cancer treatment.
{"title":"DNA-targeting ruthenium(II) complexes that simultaneously induce tumor apoptosis and autophagy","authors":"Yu-Yi Ling , Liang Hao , Chunping Liao , Yujun He , Yinting Hu , Zitong Peng , Zhiyi Li , Lanmei Chen , Yongcun Wang , Jincan Chen","doi":"10.1016/j.jinorgbio.2026.113247","DOIUrl":"10.1016/j.jinorgbio.2026.113247","url":null,"abstract":"<div><div>DNA damage is a critical approach in cancer therapy, and the regulation of the cell cycle to inhibit cell proliferation has become an important therapeutic strategy. In this study, two ruthenium(II) complexes, [Ru(phen)₂(1-(p-tolyl)-9H-pyrido[3,4-<em>b</em>]indole)]PF₆ (<strong>Ru1</strong>) and [Ru(phen)₂(1-(4-chlorophenyl)-9H-pyrido[3,4-<em>b</em>]indole)]PF₆ (<strong>Ru2</strong>), featuring β-carboline as the primary ligand, were designed and synthesized. The results demonstrated that both <strong>Ru1</strong> and <strong>Ru2</strong> exhibit significant antitumor activity <em>in vitro</em>. These complexes can bind to DNA in the cell nucleus, induce DNA damage through reactive oxygen species (ROS) generation, and cause S-phase cell cycle arrest. Furthermore, <strong>Ru1</strong> effectively triggers autophagy in tumor cells. Ultimately, these mechanisms collectively lead to apoptosis. In summary, we report a DNA-targeting ruthenium complex capable of efficiently inducing DNA damage, promoting autophagy and apoptosis in tumor cells, thereby exerting potent antitumor effects. This work provides a novel strategy for cancer treatment.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113247"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-02-04DOI: 10.1016/j.jinorgbio.2026.113256
Žiko Milanović , Ali N. Hmedat , Kristina Milisavljević , Emina Mrkalić , Jovana Matić , Marijana Kosanić , Goran N. Kaluđerović
Organotin(IV) compounds remain promising anticancer candidates owing to their strong cytotoxicity and tunable structural properties. In this study, a series of (alkyl-ω-ol)triphenyltin(IV) derivatives Ph3SnL (L = alkyl-ω-ol: L1 = propyl-3-ol, L2 = butyl-4-ol; L3 = octyl-8-ol; L4 = dodecyl-11-ol) was evaluated against human cancer cell lines (T47D, RKO, SAS, ES2). MTT and crystal violet (CV) assays demonstrated pronounced cytotoxic effects, with Ph3SnL3 among the most active analogues, particularly in the most responsive models (RKO and SAS). Mechanistic investigations indicated apoptosis induction, cell-cycle perturbation, autophagy activation, and elevated intracellular ROS levels as key contributors to the cytotoxic response. Considering the overexpression of transferrin receptor 1 (TfR1) in malignant cells, the interaction of Ph3SnL3 with transferrin (Tf) was further examined. Fluorescence quenching analyses combined with molecular docking revealed that Ph3SnL3 can be accommodated within both lobes of Tf, with a distinct preference for the C-lobe, reflecting higher structural complementarity within this binding region. Antimicrobial screening indicated negligible activity, supporting desirable selectivity toward tumour cells. Altogether, this multimodal experimental–computational study demonstrates that (alkyl-ω-ol)triphenyltin(IV) complexes exert anticancer effects through a combination of direct cytotoxic mechanisms and Tf-assisted protein binding pathways, providing a basis for the rational development of organotin(IV)-based metallodrugs with improved selectivity.
{"title":"Multimodal insights into the anticancer activity of (alkyl-ω-ol)triphenyltin(IV) compounds: Targeting cancer pathways through cytotoxicity and transferrin-gateway interaction mechanisms","authors":"Žiko Milanović , Ali N. Hmedat , Kristina Milisavljević , Emina Mrkalić , Jovana Matić , Marijana Kosanić , Goran N. Kaluđerović","doi":"10.1016/j.jinorgbio.2026.113256","DOIUrl":"10.1016/j.jinorgbio.2026.113256","url":null,"abstract":"<div><div>Organotin(IV) compounds remain promising anticancer candidates owing to their strong cytotoxicity and tunable structural properties. In this study, a series of (alkyl-ω-ol)triphenyltin(IV) derivatives <strong>Ph</strong><sub><strong>3</strong></sub><strong>SnL</strong> (L = alkyl-ω-ol: <strong>L1</strong> = propyl-3-ol, <strong>L2</strong> = butyl-4-ol; <strong>L3</strong> = octyl-8-ol; <strong>L4</strong> = dodecyl-11-ol) was evaluated against human cancer cell lines (T47D, RKO, SAS, ES2). MTT and crystal violet (CV) assays demonstrated pronounced cytotoxic effects, with <strong>Ph</strong><sub><strong>3</strong></sub><strong>SnL</strong><sub><strong>3</strong></sub> among the most active analogues, particularly in the most responsive models (RKO and SAS). Mechanistic investigations indicated apoptosis induction, cell-cycle perturbation, autophagy activation, and elevated intracellular ROS levels as key contributors to the cytotoxic response. Considering the overexpression of transferrin receptor 1 (<strong>TfR1</strong>) in malignant cells, the interaction of <strong>Ph</strong><sub><strong>3</strong></sub><strong>SnL</strong><sub><strong>3</strong></sub> with transferrin (<strong>Tf</strong>) was further examined. Fluorescence quenching analyses combined with molecular docking revealed that <strong>Ph</strong><sub><strong>3</strong></sub><strong>SnL</strong><sub><strong>3</strong></sub> can be accommodated within both lobes of <strong>Tf</strong>, with a distinct preference for the C-lobe, reflecting higher structural complementarity within this binding region. Antimicrobial screening indicated negligible activity, supporting desirable selectivity toward tumour cells. Altogether, this multimodal experimental–computational study demonstrates that (alkyl-ω-ol)triphenyltin(IV) complexes exert anticancer effects through a combination of direct cytotoxic mechanisms and <strong>Tf</strong>-assisted protein binding pathways, providing a basis for the rational development of organotin(IV)-based metallodrugs with improved selectivity.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113256"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-01-22DOI: 10.1016/j.jinorgbio.2026.113239
Matheus Torelli Martin, Naiara Cristina Bessas, César Augusto Peña Llontop, Germán Gustavo Sgro, Roberto Santana da Silva
Porphyrins substituted with ruthenium(II) complexes have emerged as promising photosensitizers for photodynamic therapy (PDT) due to their tunable photophysical properties and potential for multimodal reactivity. Here, we investigate the interaction of a meso-substituted nitro‑ruthenium porphyrin complex (RuNO2TPyP) with human serum albumin (HSA) and deoxyribonucleic acid (DNA), as well as its DNA photocleavage capability. Ultraviolet visible (UV–Vis) and fluorescence spectroscopy revealed that RuNO2TPyP binds spontaneously to HSA with moderate affinity (Binding constant (Kb) ≈ 103 M−1), driven predominantly by hydrophobic forces. Fluorescence quenching analyses and Förster resonance energy transfer (FRET) suggested close proximity between the complex and the Tryptophan-214 (Trp-214) residue, with fluorescence quenching mainly governed by a static quenching mechanism. Interaction with DNA induced hypochromism and bathochromic shifts in the Soret band, consistent with groove-binding and partial intercalation modes
(Kb ≈ 3 × 104 M−1). Competitive binding assays with ethidium bromide (EB) and 4′,6-diamidine-2-phenylindole (DAPI) confirmed strong DNA association and preferential groove interaction. Importantly, RuNO2TPyP promoted light-dependent plasmid DNA cleavage under 400 nm irradiation, generating strand breaks without dark toxicity. Together, these results demonstrate that RuNO2TPyP displays moderate biomolecular affinity, effective photoreactivity, and oxygen-dependent DNA damage, supporting its potential as a phototherapeutic agent for PDT applications.
{"title":"Dual HSA and DNA affinity of a free-base porphyrin nitro-ruthenium(II) complex: Spectroscopic evaluation and photocleavage studies","authors":"Matheus Torelli Martin, Naiara Cristina Bessas, César Augusto Peña Llontop, Germán Gustavo Sgro, Roberto Santana da Silva","doi":"10.1016/j.jinorgbio.2026.113239","DOIUrl":"10.1016/j.jinorgbio.2026.113239","url":null,"abstract":"<div><div>Porphyrins substituted with ruthenium(II) complexes have emerged as promising photosensitizers for photodynamic therapy (PDT) due to their tunable photophysical properties and potential for multimodal reactivity. Here, we investigate the interaction of a meso-substituted nitro‑ruthenium porphyrin complex (RuNO<sub>2</sub>TPyP) with human serum albumin (HSA) and deoxyribonucleic acid (DNA), as well as its DNA photocleavage capability. Ultraviolet visible (UV–Vis) and fluorescence spectroscopy revealed that RuNO<sub>2</sub>TPyP binds spontaneously to HSA with moderate affinity (Binding constant (<em>K</em><sub>b</sub>) ≈ 10<sup>3</sup> M<sup>−1</sup>), driven predominantly by hydrophobic forces. Fluorescence quenching analyses and Förster resonance energy transfer (FRET) suggested close proximity between the complex and the Tryptophan-214 (Trp-214) residue, with fluorescence quenching mainly governed by a static quenching mechanism. Interaction with DNA induced hypochromism and bathochromic shifts in the Soret band, consistent with groove-binding and partial intercalation modes</div><div>(<em>K</em><sub>b</sub> ≈ 3 × 10<sup>4</sup> M<sup>−1</sup>). Competitive binding assays with ethidium bromide (EB) and 4′,6-diamidine-2-phenylindole (DAPI) confirmed strong DNA association and preferential groove interaction. Importantly, RuNO<sub>2</sub>TPyP promoted light-dependent plasmid DNA cleavage under 400 nm irradiation, generating strand breaks without dark toxicity. Together, these results demonstrate that RuNO<sub>2</sub>TPyP displays moderate biomolecular affinity, effective photoreactivity, and oxygen-dependent DNA damage, supporting its potential as a phototherapeutic agent for PDT applications.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113239"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-02-07DOI: 10.1016/j.jinorgbio.2026.113254
Marayke Mayrata , Alvaro Lopez-Sanchez , Esteban P. Urriolabeitia , Sophie McCarrick , Aaron Manu , Javier E. López-Hernández , Michelle C. Neary , Maria Contel
Chemical stability and metal speciation are key determinants of the biological behavior and translational potential of metal-based chemotherapeutic agents, for which ligand exchange and chemical transformation frequently occur under physiological conditions. In these systems, pharmacological activity is defined not by a single molecular entity but by the distribution and interconversion of metal-containing species in solution and biological media. Here, we investigate the time-dependent speciation of the highly water-soluble ruthenium complex [(η6-p-cymene)Ru(κ-N,O–Ph₃P=N–CO–2-NC₅H₄)]Cl (Ru-IM), which exhibits a shelf life exceeding two years and has demonstrated robust anticancer efficacy in preclinical mechanistic and pharmacokinetic studies in triple-negative breast cancer mouse models. Using NMR spectroscopy, we characterized Ru-IM speciation in D₂O, deuterated phosphate-buffered saline, deuterated Dulbecco's Modified Eagle's Medium (DMEM), and DMEM supplemented with fetal bovine serum. Two dominant speciation pathways were identified: (A) hydrolysis with loss of O=PPh₃ from the IM ligand, which results in loss of anticancer activity, and (B) ruthenium cyclometallation of a phenyl group from the IM ligand, which preserves biological activity. The relative distribution of these species is strongly influenced by concentration, temperature, and medium composition. Notably, Ru-IM remains the predominant species in aqueous solution for at least 24 h, with stability extendable to several days under optimized storage conditions. Collectively, these results support a prodrug activation model, in which Ru-IM undergoes controlled speciation under biologically relevant conditions to generate an active cyclometalated ruthenium species.
化学稳定性和金属形态形成是金属基化疗药物生物学行为和翻译潜力的关键决定因素，在生理条件下，配体交换和化学转化经常发生。在这些系统中，药理活性不是由单个分子实体定义的，而是由溶液和生物介质中含金属物种的分布和相互转化定义的。在这里，我们研究了高水溶性钌配合物[(η - 6- P -cymene)Ru（κ-N,O-Ph₃P=N-CO-2-NC₅H₄）]Cl （Ru- im）的时间依赖性形态，其保质期超过两年，并在三阴性乳腺癌小鼠模型的临床前机制和药代动力学研究中显示出强大的抗癌功效。利用核磁共振波谱，我们表征了Ru-IM在脱氧核糖核酸、氘化磷酸盐缓冲盐水、氘化Dulbecco's Modified Eagle's Medium （DMEM）和添加胎牛血清的DMEM中的形态。确定了两种主要的物种形成途径：(A) IM配体上O=PPh₃的水解损失，导致抗癌活性的丧失；(B) IM配体上苯基的钌环金属化，保持了生物活性。这些物种的相对分布受浓度、温度和介质组成的强烈影响。值得注意的是，Ru-IM在水溶液中至少保持24小时的优势物质，在优化的储存条件下稳定性可扩展至数天。总的来说，这些结果支持药物前激活模型，其中Ru-IM在生物学相关条件下经历受控的物种形成，以产生活性环金属化钌物种。
{"title":"NMR spectroscopy stability studies of Ru-IM, a prodrug candidate for triple negative breast cancer","authors":"Marayke Mayrata , Alvaro Lopez-Sanchez , Esteban P. Urriolabeitia , Sophie McCarrick , Aaron Manu , Javier E. López-Hernández , Michelle C. Neary , Maria Contel","doi":"10.1016/j.jinorgbio.2026.113254","DOIUrl":"10.1016/j.jinorgbio.2026.113254","url":null,"abstract":"<div><div>Chemical stability and metal speciation are key determinants of the biological behavior and translational potential of metal-based chemotherapeutic agents, for which ligand exchange and chemical transformation frequently occur under physiological conditions. In these systems, pharmacological activity is defined not by a single molecular entity but by the distribution and interconversion of metal-containing species in solution and biological media. Here, we investigate the time-dependent speciation of the highly water-soluble ruthenium complex [(η<sup>6</sup>-<em>p</em>-cymene)Ru(κ-N,O–Ph₃P=N–CO–2-NC₅H₄)]Cl (<strong>Ru-IM</strong>), which exhibits a shelf life exceeding two years and has demonstrated robust anticancer efficacy in preclinical mechanistic and pharmacokinetic studies in triple-negative breast cancer mouse models. Using NMR spectroscopy, we characterized <strong>Ru-IM</strong> speciation in D₂O, deuterated phosphate-buffered saline, deuterated Dulbecco's Modified Eagle's Medium (DMEM), and DMEM supplemented with fetal bovine serum. Two dominant speciation pathways were identified: (A) hydrolysis with loss of O=PPh₃ from the IM ligand, which results in loss of anticancer activity, and (B) ruthenium cyclometallation of a phenyl group from the IM ligand, which preserves biological activity. The relative distribution of these species is strongly influenced by concentration, temperature, and medium composition. Notably, <strong>Ru-IM</strong> remains the predominant species in aqueous solution for at least 24 h, with stability extendable to several days under optimized storage conditions. Collectively, these results support a prodrug activation model, in which <strong>Ru-IM</strong> undergoes controlled speciation under biologically relevant conditions to generate an active cyclometalated ruthenium species.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113254"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-02-05DOI: 10.1016/j.jinorgbio.2026.113257
Paolo Santucci , Frédéric Biaso , Jérôme Becam , Ludovic Dubard , Marianne Ilbert , Benjamin Ezraty , Ievgen Mazurenko , Elisabeth Lojou , Umberto Contaldo
CueOs are multicopper oxidases (MCOs) involved in key biological processes related to copper homeostasis. Their physiological function is the catalytic oxidation of toxic cuprous ions (Cu+) to cupric ions (Cu2+), coupled with the reduction of O2 to water. In addition to the copper sites belonging to the classical electron transfer chain of MCOs, from Cu-T1 to the trinuclear cluster (TNC), a Cu8-site was previously identified in EcCueO crystal structures, located in close proximity to TNC. One conserved ligand of the Cu8-site is the amino acid H145, in both Cu+ and Cu2+ redox states. By designing and characterizing the H145S variant, this work demonstrates for the first time the pivotal role of H145 in the functional maturation/metalation of EcCueO active sites under conditions of low Cu2+/Cu+ availability. Moreover, we show that H145 is part of a conserved HxHxH motif in CueOs, and more generally in bacterial MCOs, suggesting a common copper-binding Cu8-site for metalation in vivo. The absence of this conserved motif in certain MCOs, or the presence of additional His/Met-rich or His-rich insertions, appears to be linked to cellular copper availability and highlights the adaptability of MCOs. Beyond this fundamental understanding of MCO metalation mechanism, this works paves the way for application in medicine and environmental copper detection.
{"title":"A conserved copper-binding site in multicopper oxidases regulates the metalation of CueO from Escherichia coli","authors":"Paolo Santucci , Frédéric Biaso , Jérôme Becam , Ludovic Dubard , Marianne Ilbert , Benjamin Ezraty , Ievgen Mazurenko , Elisabeth Lojou , Umberto Contaldo","doi":"10.1016/j.jinorgbio.2026.113257","DOIUrl":"10.1016/j.jinorgbio.2026.113257","url":null,"abstract":"<div><div>CueOs are multicopper oxidases (MCOs) involved in key biological processes related to copper homeostasis. Their physiological function is the catalytic oxidation of toxic cuprous ions (Cu<sup>+</sup>) to cupric ions (Cu<sup>2+</sup>), coupled with the reduction of O<sub>2</sub> to water. In addition to the copper sites belonging to the classical electron transfer chain of MCOs, from Cu-T1 to the trinuclear cluster (TNC), a Cu8-site was previously identified in <em>Ec</em>CueO crystal structures, located in close proximity to TNC. One conserved ligand of the Cu8-site is the amino acid H<sub>145</sub>, in both Cu<sup>+</sup> and Cu<sup>2+</sup> redox states. By designing and characterizing the H<sub>145</sub>S variant, this work demonstrates for the first time the pivotal role of H<sub>145</sub> in the functional maturation/metalation of <em>Ec</em>CueO active sites under conditions of low Cu<sup>2+</sup>/Cu<sup>+</sup> availability. Moreover, we show that H<sub>145</sub> is part of a conserved HxHxH motif in CueOs, and more generally in bacterial MCOs, suggesting a common copper-binding Cu8-site for metalation <em>in vivo</em>. The absence of this conserved motif in certain MCOs, or the presence of additional His/Met-rich or His-rich insertions, appears to be linked to cellular copper availability and highlights the adaptability of MCOs. Beyond this fundamental understanding of MCO metalation mechanism, this works paves the way for application in medicine and environmental copper detection.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113257"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-01-17DOI: 10.1016/j.jinorgbio.2026.113227
Agnieszka Mierek-Adamska , Jose Gutierrez-Marcos , Claudia A. Blindauer
Zinc and cadmium share similar chemical properties; however, while zinc is an indispensable microelement involved in several physiological processes, cadmium is highly toxic. Cadmium toxicity results at least to some extent from replacing zinc (and other metals) from their active sites in enzymes and other proteins. This highlights why the correct population of metalloproteins with metals is crucial for proper cellular metabolism. In the face of growing demand for food, both in terms of quantity and quality, a rapid development of crop cultivars containing a higher amount of bioavailable zinc in the edible parts of plants, crucially without the simultaneous accumulation of cadmium, is imperative. Type 4 plant metallothioneins (pMT4s) are seed-specific proteins for which a potential role as a zinc specificity filter has been proposed. It was suggested that two conserved histidine residues are key for discrimination between zinc and cadmium. In this study, we analysed the metal-binding properties of Sorghum bicolor pMT4 (SbMT4) wild-type and mutant proteins with histidine/s replaced by tyrosine/s (H32Y, H40Y, and H32Y/H40Y) using mass spectrometry, elemental analysis, and NMR spectroscopy. SbMT4 is a Zn-thionein, but unexpectedly, it was also fully folded in the presence of cadmium – owing to a zinc ion remaining in the mononuclear Cys2His2 site in domain II. All three mutant proteins were misfolded in the presence of either zinc or cadmium, but increased Cd-to-protein stoichiometry was observed. The presence of histidines impacted SbMT4 metal selectivity when expressed in bacterial cells, but did not affect Zn/Cd accumulation in transgenic Arabidopsis thaliana plants.
{"title":"Histidines promote zinc over cadmium binding to the single type 4 metallothionein from Great Millet (Sorghum bicolor)","authors":"Agnieszka Mierek-Adamska , Jose Gutierrez-Marcos , Claudia A. Blindauer","doi":"10.1016/j.jinorgbio.2026.113227","DOIUrl":"10.1016/j.jinorgbio.2026.113227","url":null,"abstract":"<div><div>Zinc and cadmium share similar chemical properties; however, while zinc is an indispensable microelement involved in several physiological processes, cadmium is highly toxic. Cadmium toxicity results at least to some extent from replacing zinc (and other metals) from their active sites in enzymes and other proteins. This highlights why the correct population of metalloproteins with metals is crucial for proper cellular metabolism. In the face of growing demand for food, both in terms of quantity and quality, a rapid development of crop cultivars containing a higher amount of bioavailable zinc in the edible parts of plants, crucially without the simultaneous accumulation of cadmium, is imperative. Type 4 plant metallothioneins (pMT4s) are seed-specific proteins for which a potential role as a zinc specificity filter has been proposed. It was suggested that two conserved histidine residues are key for discrimination between zinc and cadmium. In this study, we analysed the metal-binding properties of <em>Sorghum bicolor</em> pMT4 (SbMT4) wild-type and mutant proteins with histidine/s replaced by tyrosine/s (H32Y, H40Y, and H32Y/H40Y) using mass spectrometry, elemental analysis, and NMR spectroscopy. SbMT4 is a Zn-thionein, but unexpectedly, it was also fully folded in the presence of cadmium – owing to a zinc ion remaining in the mononuclear Cys<sub>2</sub>His<sub>2</sub> site in domain II. All three mutant proteins were misfolded in the presence of either zinc or cadmium, but increased Cd-to-protein stoichiometry was observed. The presence of histidines impacted SbMT4 metal selectivity when expressed in bacterial cells, but did not affect Zn/Cd accumulation in transgenic <em>Arabidopsis thaliana</em> plants.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113227"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-02-06DOI: 10.1016/j.jinorgbio.2026.113245
Xiang Zhou , Lijun Zhang , Jie Zhi , Lihua Zhao , Rui Shen , Aihong Yang , Xiaodi Kou
Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathogenesis. Currently, there are still no drugs on the market that have a significant therapeutic effect. Zinc, an essential trace element, played a double-edged role in neuronal function—zinc deficiency accelerated cognitive decline and neurodegeneration, however overloaded zinc may cause β-amyloid (Aβ) aggregation. In contrast, the brains of AD patients exhibited significantly elevated copper concentrations around Aβ plaques, where this localized high copper concentration microenvironment catalyzed oxidative reactions and Aβ aggregation, thereby exacerbating neuronal damage. To address the interconnected pathological targets, a novel carbamate porphyrin derivative (1) and its zinc complex (1-Zn) were designed and synthesized. Single crystals of both compounds were successfully obtained and analyzed. And with further Hirshfeld surface analysis, molecular dynamics predictions and frontier molecular orbital studies, their structure characteristics and intermolecular interactions were systematically analyzed. Subsequently, metal chelation assays, antioxidant activity evaluations, Aβ aggregation inhibition assays, and anticholinesterase assays were performed to assess the multi-target therapeutic potential. Notably, 1-Zn exhibited a dual-function metal dyshomeostasis regulation ability, namely, chelating excess Cu2+ and at the same time releasing a specific amount of Zn2+ to the system. In addition, 1 and 1-Zn showed comparable ROS scavenging ability (in vitro and in vivo) and Aβ aggregation inhibition ability to the positive control drugs. 1-Zn also showed similar cholinesterase inhibition activity as rivastigmine. Consequently, this study demonstrated that 1 and 1-Zn held potential as multifunctional anti-AD agents, meriting further investigation for clinical translation.
{"title":"Zinc-porphyrin complex as multifunctional anti-AD agent: Synthesis, X-ray single crystal analysis and activity study","authors":"Xiang Zhou , Lijun Zhang , Jie Zhi , Lihua Zhao , Rui Shen , Aihong Yang , Xiaodi Kou","doi":"10.1016/j.jinorgbio.2026.113245","DOIUrl":"10.1016/j.jinorgbio.2026.113245","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathogenesis. Currently, there are still no drugs on the market that have a significant therapeutic effect. Zinc, an essential trace element, played a double-edged role in neuronal function—zinc deficiency accelerated cognitive decline and neurodegeneration, however overloaded zinc may cause β-amyloid (Aβ) aggregation. In contrast, the brains of AD patients exhibited significantly elevated copper concentrations around Aβ plaques, where this localized high copper concentration microenvironment catalyzed oxidative reactions and Aβ aggregation, thereby exacerbating neuronal damage. To address the interconnected pathological targets, a novel carbamate porphyrin derivative (<strong>1</strong>) and its zinc complex (<strong>1</strong>-Zn) were designed and synthesized. Single crystals of both compounds were successfully obtained and analyzed. And with further Hirshfeld surface analysis, molecular dynamics predictions and frontier molecular orbital studies, their structure characteristics and intermolecular interactions were systematically analyzed. Subsequently, metal chelation assays, antioxidant activity evaluations, Aβ aggregation inhibition assays, and anticholinesterase assays were performed to assess the multi-target therapeutic potential. Notably, <strong>1</strong>-Zn exhibited a dual-function metal dyshomeostasis regulation ability, namely, chelating excess Cu<sup>2+</sup> and at the same time releasing a specific amount of Zn<sup>2+</sup> to the system. In addition, <strong>1</strong> and <strong>1</strong>-Zn showed comparable ROS scavenging ability (in vitro and in vivo) and Aβ aggregation inhibition ability to the positive control drugs. <strong>1</strong>-Zn also showed similar cholinesterase inhibition activity as rivastigmine. Consequently, this study demonstrated that <strong>1</strong> and <strong>1</strong>-Zn held potential as multifunctional anti-AD agents, meriting further investigation for clinical translation.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113245"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146185495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-01-17DOI: 10.1016/j.jinorgbio.2026.113236
Xing-Yi Zhu , Zhen-Lang Xie , Si-Yuan Wang , Wan-Ting Jin , Zhao-Hui Zhou
Enantiomerically pure iron(II/III) lactates Λ-FeII(S-Hlact)2(H2O)2 (1), Na[Λ-FeIII(S-Hlact)2(S-lact)]·3.5H2O (2a) and Na[Δ-FeIII(R-Hlact)2(R-lact)]·3.5H2O (2b), along with iron(II/III) citrates (H2pz)2[FeIII2(cit)2(H2O)2]·2H2O (3) and [FeII(Hpz)4]n[FeIII2(cit)2(Hpz)2]n·2n(Hpz)·0.25nH2O (4) (H2lact = lactic acid, H4cit = citric acid, Hpz = pyrazole) have been obtained. In 1 and 2, lactates chelate with iron bidentately through α-hydroxy/α-alkoxy and α-carboxy groups, respectively, forming stable five-membered chelated rings. Strong intermolecular hydrogen bonds have been found between α-hydroxy and α-alkoxy groups, with strong electron delocalization. For 3, citrate chelates one of the iron centers in a tridentate mode via its α-alkoxy, α-carboxy, and β-carboxy groups, leaving protonated pyrazole free. Further substitution of the coordinated water molecule in 3 results in the formation of mixed-valent pyrazole iron(II/III) citrate 4. The iron lactates and citrates show resemblance to the local environment of the active site of homocitrate and imidazole-coordinated FeFe-cofactor in Fe-only nitrogenase. The biological relevance has been discussed in details.
{"title":"Iron(II/III) α-hydroxycarboxylates toward the local coordination environments of FeFe-cofactor in Fe‑nitrogenase","authors":"Xing-Yi Zhu , Zhen-Lang Xie , Si-Yuan Wang , Wan-Ting Jin , Zhao-Hui Zhou","doi":"10.1016/j.jinorgbio.2026.113236","DOIUrl":"10.1016/j.jinorgbio.2026.113236","url":null,"abstract":"<div><div>Enantiomerically pure iron(II/III) lactates Λ-Fe<sup>II</sup>(<em>S</em>-Hlact)<sub>2</sub>(H<sub>2</sub>O)<sub>2</sub> (<strong>1</strong>), Na[Λ-Fe<sup>III</sup>(<em>S</em>-Hlact)<sub>2</sub>(<em>S</em>-lact)]·3.5H<sub>2</sub>O (<strong>2a</strong>) and Na[Δ-Fe<sup>III</sup>(<em>R</em>-Hlact)<sub>2</sub>(<em>R</em>-lact)]·3.5H<sub>2</sub>O (<strong>2b</strong>), along with iron(II/III) citrates (H<sub>2</sub>pz)<sub>2</sub>[Fe<sup>III</sup><sub>2</sub>(cit)<sub>2</sub>(H<sub>2</sub>O)<sub>2</sub>]·2H<sub>2</sub>O (<strong>3</strong>) and [Fe<sup>II</sup>(Hpz)<sub>4</sub>]<sub>n</sub>[Fe<sup>III</sup><sub>2</sub>(cit)<sub>2</sub>(Hpz)<sub>2</sub>]<sub>n</sub>·2n(Hpz)·0.25nH<sub>2</sub>O (<strong>4</strong>) (H<sub>2</sub>lact = lactic acid, H<sub>4</sub>cit = citric acid, Hpz = pyrazole) have been obtained. In <strong>1</strong> and <strong>2</strong>, lactates chelate with iron bidentately through α-hydroxy/α-alkoxy and α-carboxy groups, respectively, forming stable five-membered chelated rings. Strong intermolecular hydrogen bonds have been found between α-hydroxy and α-alkoxy groups, with strong electron delocalization. For <strong>3</strong>, citrate chelates one of the iron centers in a tridentate mode <em>via</em> its α-alkoxy, α-carboxy, and β-carboxy groups, leaving protonated pyrazole free. Further substitution of the coordinated water molecule in <strong>3</strong> results in the formation of mixed-valent pyrazole iron(II/III) citrate <strong>4</strong>. The iron lactates and citrates show resemblance to the local environment of the active site of homocitrate and imidazole-coordinated FeFe-cofactor in Fe-only nitrogenase. The biological relevance has been discussed in details.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113236"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-01-17DOI: 10.1016/j.jinorgbio.2026.113237
Alissa Lance-Byrne , Juliet C. Gee , Timothy C. Johnstone
Sodium stibogluconate is an effective but toxic Sb-containing antileishmanial drug. Despite having been in clinical use for over half a century, the chemical structure of this small-molecule drug remains unknown. Historically, the drug has been thought to comprise an intractable mixture of interconverting species. We report here nuclear magnetic resonance (NMR) spectroscopic experiments that provide the first evidence that the reaction between gluconate and [Sb(OH)6]− produces primarily one molecular species. Multidimensional experiments allow the NMR resonances of this species to be fully assigned. Further experiments on authentic samples and clinical preparations of sodium stibogluconate confirm that the primary product of the reaction of gluconate and [Sb(OH)6]− is the predominant antimony-containing component of the drug. The thermodynamic stability of this predominant species was assessed using a combination of 1H and 121Sb NMR spectroscopic measurements, which afforded a value of K = 1006 M−1 for its formation from gluconate and [Sb(OH)6]−.
{"title":"NMR spectroscopic evidence that the antileishmanial drug sodium stibogluconate comprises one predominant molecular species","authors":"Alissa Lance-Byrne , Juliet C. Gee , Timothy C. Johnstone","doi":"10.1016/j.jinorgbio.2026.113237","DOIUrl":"10.1016/j.jinorgbio.2026.113237","url":null,"abstract":"<div><div>Sodium stibogluconate is an effective but toxic Sb-containing antileishmanial drug. Despite having been in clinical use for over half a century, the chemical structure of this small-molecule drug remains unknown. Historically, the drug has been thought to comprise an intractable mixture of interconverting species. We report here nuclear magnetic resonance (NMR) spectroscopic experiments that provide the first evidence that the reaction between gluconate and [Sb(OH)<sub>6</sub>]<sup>−</sup> produces primarily one molecular species. Multidimensional experiments allow the NMR resonances of this species to be fully assigned. Further experiments on authentic samples and clinical preparations of sodium stibogluconate confirm that the primary product of the reaction of gluconate and [Sb(OH)<sub>6</sub>]<sup>−</sup> is the predominant antimony-containing component of the drug. The thermodynamic stability of this predominant species was assessed using a combination of <sup>1</sup>H and <sup>121</sup>Sb NMR spectroscopic measurements, which afforded a value of <em>K</em> = 1006 M<sup>−1</sup> for its formation from gluconate and [Sb(OH)<sub>6</sub>]<sup>−</sup>.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113237"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-01-22DOI: 10.1016/j.jinorgbio.2026.113241
Yong-Sheng Yang , Hou Zhu , Chun-Rong Jiang, Zheng Zhang, Meng-Ting Xu, Rong-Tao Li, Rui-Rong Ye
Transition metal iridium(III) and ruthenium(II) complexes exhibit significant anti-tumor potential. Vadimezan (VDA) is a potent non-nucleotide stimulator of interferon genes (STING) agonist that enhances the efficacy of tumor immunotherapy. Herein, we designed and synthesized three iridium(III) (Ir-VDA-1–3, C^N = 2-phenylpyridine (ppy, in Ir-VDA-1), 2-(2-thienyl)pyridine (thpy, in Ir-VDA-2), and 2-(2,4-difluorophenyl)pyridine (dfppy, in Ir-VDA-3)) and three ruthenium(II) (Ru-VDA-1–3, N^N = 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru-VDA-1), 1,10-phenanthroline (phen, in Ru-VDA-2), and 2,2′-bipyridine (bpy, in Ru-VDA-3)) complexes by incorporating VDA with iridium(III) and ruthenium(II) complexes. Among of these, Ir-VDA-1–3 exhibited potent antitumor activity. Ir-VDA-1–3 were effectively internalized by mouse triple negative breast cancer (TNBC) 4T1 cells and localized to mitochondria, inducing mitochondrial pathway-mediated apoptosis. Western blot analysis revealed that Ir-VDA-1–3 activated and cleaved caspase 3, subsequently cleaving GSDME to induce pyroptosis. Notably, Ir-VDA-1–3 treatment significantly upregulated the expression of key proteins (cyclic GMP-AMP synthase (cGAS) and phosphorylated STING (p-STING)) in the cGAS-STING signaling pathway. Furthermore, Ir-VDA-1–3 functioned as the immunogenic cell death (ICD) inducers, promoting damage-associated molecular patterns (DAMPs) release, including calreticulin (CRT), high mobility group protein 1 (HMGB1), and adenosine triphosphate (ATP). This strategy provides a novel design concept for multimodal synergistic cancer therapy.
过渡金属铱（III）和钌（II）配合物具有显著的抗肿瘤潜能。Vadimezan （VDA）是一种有效的干扰素基因非核苷酸刺激剂（STING）激动剂，可提高肿瘤免疫治疗的疗效。本文设计并合成了三个铱（III） (Ir-VDA-1 -3, C^N = 2-苯基吡啶（py, in Ir-VDA-1）、2-（2-噻吩基）吡啶（thpy, in Ir-VDA-2）、2-（2,4-二氟苯基）吡啶（dppy, in Ir-VDA-3）和三个钌（II） （Ru-VDA-1 -3, N^N = 4,7-二苯基-1,10-菲罗啉（DIP, in Ru-VDA-1）、1,10-菲罗啉（phen, in Ru-VDA-2）和2,2 ' -联吡啶（bpy, in Ru-VDA-3））配合物。其中，Ir-VDA-1-3具有较强的抗肿瘤活性。Ir-VDA-1-3被小鼠三阴性乳腺癌（TNBC） 4T1细胞有效内化并定位于线粒体，诱导线粒体途径介导的细胞凋亡。Western blot分析显示，Ir-VDA-1-3激活并切割caspase 3，随后切割GSDME导致焦亡。值得注意的是，Ir-VDA-1-3处理显著上调了cGAS-STING信号通路中关键蛋白（环GMP-AMP合成酶（cGAS）和磷酸化STING (p-STING)）的表达。此外，Ir-VDA-1-3作为免疫原性细胞死亡（ICD）诱导剂，促进损伤相关分子模式（DAMPs）的释放，包括钙网蛋白（CRT）、高迁移率组蛋白1 （HMGB1）和三磷酸腺苷（ATP）。该策略为多模式协同癌症治疗提供了一种新的设计理念。
{"title":"Design, synthesis, and antitumor mechanism investigation of iridium(III)/ruthenium(II)-vadimezan conjugates towards 4T1 cells","authors":"Yong-Sheng Yang , Hou Zhu , Chun-Rong Jiang, Zheng Zhang, Meng-Ting Xu, Rong-Tao Li, Rui-Rong Ye","doi":"10.1016/j.jinorgbio.2026.113241","DOIUrl":"10.1016/j.jinorgbio.2026.113241","url":null,"abstract":"<div><div>Transition metal iridium(III) and ruthenium(II) complexes exhibit significant anti-tumor potential. Vadimezan (VDA) is a potent non-nucleotide stimulator of interferon genes (STING) agonist that enhances the efficacy of tumor immunotherapy. Herein, we designed and synthesized three iridium(III) (<strong>Ir-VDA-1</strong>–<strong>3</strong>, C^N = 2-phenylpyridine (ppy, in <strong>Ir-VDA-1</strong>), 2-(2-thienyl)pyridine (thpy, in <strong>Ir-VDA-2</strong>), and 2-(2,4-difluorophenyl)pyridine (dfppy, in <strong>Ir-VDA-3</strong>)) and three ruthenium(II) (<strong>Ru-VDA-1</strong>–<strong>3</strong>, N^N = 4,7-diphenyl-1,10-phenanthroline (DIP, in <strong>Ru-VDA-1</strong>), 1,10-phenanthroline (phen, in <strong>Ru-VDA-2</strong>), and 2,2′-bipyridine (bpy, in <strong>Ru-VDA-3</strong>)) complexes by incorporating VDA with iridium(III) and ruthenium(II) complexes. Among of these, <strong>Ir-VDA-1</strong>–<strong>3</strong> exhibited potent antitumor activity. <strong>Ir-VDA-1</strong>–<strong>3</strong> were effectively internalized by mouse triple negative breast cancer (TNBC) 4T1 cells and localized to mitochondria, inducing mitochondrial pathway-mediated apoptosis. Western blot analysis revealed that <strong>Ir-VDA-1</strong>–<strong>3</strong> activated and cleaved caspase 3, subsequently cleaving GSDME to induce pyroptosis. Notably, <strong>Ir-VDA-1</strong>–<strong>3</strong> treatment significantly upregulated the expression of key proteins (cyclic GMP-AMP synthase (cGAS) and phosphorylated STING (p-STING)) in the cGAS-STING signaling pathway. Furthermore, <strong>Ir-VDA-1</strong>–<strong>3</strong> functioned as the immunogenic cell death (ICD) inducers, promoting damage-associated molecular patterns (DAMPs) release, including calreticulin (CRT), high mobility group protein 1 (HMGB1), and adenosine triphosphate (ATP). This strategy provides a novel design concept for multimodal synergistic cancer therapy.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113241"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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