Pub Date : 2026-04-01Epub Date: 2026-01-21DOI: 10.1016/j.jinorgbio.2026.113238
Patricia C Dos Santos, Jeffrey M Boyd
{"title":"Editorial: Special issue on iron-sulfur proteins.","authors":"Patricia C Dos Santos, Jeffrey M Boyd","doi":"10.1016/j.jinorgbio.2026.113238","DOIUrl":"10.1016/j.jinorgbio.2026.113238","url":null,"abstract":"","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":" ","pages":"113238"},"PeriodicalIF":3.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091677","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 : 2026-02-04DOI: 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":"https://doi.org/10.1016/j.jinorgbio.2026.113256","url":null,"abstract":"<p><p>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 Ph<sub>3</sub>SnL (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 Ph<sub>3</sub>SnL<sub>3</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 (TfR1) in malignant cells, the interaction of Ph<sub>3</sub>SnL<sub>3</sub> with transferrin (Tf) was further examined. Fluorescence quenching analyses combined with molecular docking revealed that Ph<sub>3</sub>SnL<sub>3</sub> 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.</p>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"113256"},"PeriodicalIF":3.2,"publicationDate":"2026-02-04","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}
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":"https://doi.org/10.1016/j.jinorgbio.2026.113247","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"113247"},"PeriodicalIF":3.2,"publicationDate":"2026-01-31","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 : 2026-01-28DOI: 10.1016/j.jinorgbio.2026.113244
Isabel B Calhau, Ana C Gomes, Sofia M Bruno, Fernanda Rosário, Laura Oliveira, Carla Pereira, Helena Oliveira, Adelaide Almeida, Isabel S Gonçalves, Martyn Pillinger
Molybdenum-based CO-releasing molecules (CORMs) are attracting interest for biological and therapeutic applications. In this work two new complexes, [Mo(η3-C3H5)X(CO)2(Hpypz)] [X = Cl (1), Br (2); Hpypz = 3-(2-pyridyl)pyrazole] have been synthesized, characterized, and evaluated for their CO-release capacity, as well as antimicrobial and anticancer potential. The evaluation of the CO-release properties by the deoxymyoglobin‑carbonmonoxymyoglobin assay showed that the two complexes are comparably slow CO releasers in aqueous systems, showing a half-life of several hours, and sustained CO release over the course of the assay (6 h). Studies of biological activity were performed with complex 1 due to its better aqueous solubility. The antibacterial activity was investigated by determination of the minimum inhibitory and minimum bactericidal concentrations with the microdilution assay for gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative Escherichia coli strains. Complex 1 displayed appreciable concentration-dependent bactericidal activity against both strains. The cytotoxicity of complex 1 was evaluated on human melanoma cells (A375) and immortalized nontumorigenic keratinocytes (HaCaT). Complex 1 exhibited selective cytotoxicity, significantly reducing the cell viability of A375 cells in a dose-dependent manner while having a lower effect on HaCaT cells, suggesting its antitumor potential against melanoma. In contrast, the precursor complex [Mo(η3-C3H5)Cl(CO)2(CH3CN)2] showed reduced activity against A375 cells and higher toxicity toward HaCaT cells, highlighting the beneficial impact of the bidentate 3-(2-pyridyl)pyrazole ligand.
{"title":"Molybdenum(II) allyl dicarbonyl complexes with 3-(2-pyridyl)pyrazole as potential CO-releasing molecules, antibacterial and antitumoral agents.","authors":"Isabel B Calhau, Ana C Gomes, Sofia M Bruno, Fernanda Rosário, Laura Oliveira, Carla Pereira, Helena Oliveira, Adelaide Almeida, Isabel S Gonçalves, Martyn Pillinger","doi":"10.1016/j.jinorgbio.2026.113244","DOIUrl":"https://doi.org/10.1016/j.jinorgbio.2026.113244","url":null,"abstract":"<p><p>Molybdenum-based CO-releasing molecules (CORMs) are attracting interest for biological and therapeutic applications. In this work two new complexes, [Mo(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)X(CO)<sub>2</sub>(Hpypz)] [X = Cl (1), Br (2); Hpypz = 3-(2-pyridyl)pyrazole] have been synthesized, characterized, and evaluated for their CO-release capacity, as well as antimicrobial and anticancer potential. The evaluation of the CO-release properties by the deoxymyoglobin‑carbonmonoxymyoglobin assay showed that the two complexes are comparably slow CO releasers in aqueous systems, showing a half-life of several hours, and sustained CO release over the course of the assay (6 h). Studies of biological activity were performed with complex 1 due to its better aqueous solubility. The antibacterial activity was investigated by determination of the minimum inhibitory and minimum bactericidal concentrations with the microdilution assay for gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative Escherichia coli strains. Complex 1 displayed appreciable concentration-dependent bactericidal activity against both strains. The cytotoxicity of complex 1 was evaluated on human melanoma cells (A375) and immortalized nontumorigenic keratinocytes (HaCaT). Complex 1 exhibited selective cytotoxicity, significantly reducing the cell viability of A375 cells in a dose-dependent manner while having a lower effect on HaCaT cells, suggesting its antitumor potential against melanoma. In contrast, the precursor complex [Mo(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)Cl(CO)<sub>2</sub>(CH<sub>3</sub>CN)<sub>2</sub>] showed reduced activity against A375 cells and higher toxicity toward HaCaT cells, highlighting the beneficial impact of the bidentate 3-(2-pyridyl)pyrazole ligand.</p>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"113244"},"PeriodicalIF":3.2,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123342","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 : 2026-01-22DOI: 10.1016/j.jinorgbio.2026.113242
Zhiheng Wang, Yiwen Wang, Ivan J. Dmochowski
Studies of ferritin biomineralization have elucidated iron loading/egress pathways and mechanisms of iron oxidation, while paying less attention to the spatiotemporal details of proton generation during iron hydrolysis. Here, we performed ferroxidase reactions with Archaeoglobus fulgidus ferritin (AfFtn) 24mer cage, which allows site-specific labeling as a dimer at low ionic strength and reassembly into a 24mer at high ionic strength. Cysteines engineered on the ferritin interior surface were covalently labeled with fluorescein-5-maleimide (F5M), which reported the dynamic changes in proton activity during ferroxidase chemistry. F5M labeled at D61C was highly responsive to proton generation and release, without being vulnerable to fluorescence quenching by Fe2+/3+. C61-F5M fluorescence quenching was maximal within 15 s of stoichiometric Fe2+ addition, and corresponded to an apparent pH value of 5.5 in the cavity. C61-F5M recovered ∼25% of the original “pre‑iron” fluorescence signal on the 5-min timescale but did not recover further with longer incubation. A complementary fluorescein-labeled peptide in bulk solution showed immediate fluorescence quenching, consistent with direct proton release from the ferroxidase center. Solution pH measurements revealed additional acidification on the 5-min timescale, consistent with the kinetics of proton egress from the ferritin cavity. The external and internal pH probes indicated that ferritin releases into solution a total of 1.6H+ for each Fe2+ oxidation, while retaining 0.4H+. This agrees with prior measurements of 2 total H+ per Fe2+ oxidation, and now reveals ferritin's propensity to accumulate protons within the protein cavity, which serves as a “brake” on iron biomineralization.
{"title":"Cavity acidification limits ferritin iron biomineralization","authors":"Zhiheng Wang, Yiwen Wang, Ivan J. Dmochowski","doi":"10.1016/j.jinorgbio.2026.113242","DOIUrl":"10.1016/j.jinorgbio.2026.113242","url":null,"abstract":"<div><div>Studies of ferritin biomineralization have elucidated iron loading/egress pathways and mechanisms of iron oxidation, while paying less attention to the spatiotemporal details of proton generation during iron hydrolysis. Here, we performed ferroxidase reactions with <em>Archaeoglobus fulgidus</em> ferritin (AfFtn) 24mer cage, which allows site-specific labeling as a dimer at low ionic strength and reassembly into a 24mer at high ionic strength. Cysteines engineered on the ferritin interior surface were covalently labeled with fluorescein-5-maleimide (F5M), which reported the dynamic changes in proton activity during ferroxidase chemistry. F5M labeled at D61C was highly responsive to proton generation and release, without being vulnerable to fluorescence quenching by Fe<sup>2+</sup>/<sup>3+</sup>. C61-F5M fluorescence quenching was maximal within 15 s of stoichiometric Fe<sup>2+</sup> addition, and corresponded to an apparent pH value of 5.5 in the cavity. C61-F5M recovered ∼25% of the original “pre‑iron” fluorescence signal on the 5-min timescale but did not recover further with longer incubation. A complementary fluorescein-labeled peptide in bulk solution showed immediate fluorescence quenching, consistent with direct proton release from the ferroxidase center. Solution pH measurements revealed additional acidification on the 5-min timescale, consistent with the kinetics of proton egress from the ferritin cavity. The external and internal pH probes indicated that ferritin releases into solution a total of 1.6H<sup>+</sup> for each Fe<sup>2+</sup> oxidation, while retaining 0.4H<sup>+</sup>. This agrees with prior measurements of 2 total H<sup>+</sup> per Fe<sup>2+</sup> oxidation, and now reveals ferritin's propensity to accumulate protons within the protein cavity, which serves as a “brake” on iron biomineralization.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113242"},"PeriodicalIF":3.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076054","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 : 2026-01-22DOI: 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":"2026-01-22","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 : 2026-01-22DOI: 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":"2026-01-22","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}
Pub Date : 2026-01-21DOI: 10.1016/j.jinorgbio.2026.113234
Dario B. Fortaleza , Josias S. Rocha , George B.S. Pereira , Tamara Teixeira , Jocely L. Dutra , Carlos A.F. Moraes , Pedro H.O. Santiago , Alzir A. Batista , Moacir R. Forim , Javier A. Ellena , Fillipe V. Rocha
Cancer remains one of the leading causes of death worldwide, with millions of new cases diagnosed annually. Cisplatin is a major advance in chemotherapy, but its severe side effects and the development of resistance limit its long-term effectiveness. In this context, palladium(II) complexes have gained attention as structural analogues of platinum compounds because they have the potential to exhibit antitumor activity while reducing toxicity. Six novel palladium(II) complexes containing thiosemicarbazide derivatives and diphosphine ligands [1,3-bis(diphenylphosphine)propane (dppp) or 1,4-bis(diphenylphosphine)butane (dppb)] were synthesized and thoroughly characterized by FTIR, 1H NMR and 31P NMR, high-resolution mass spectrometry, UV–Vis spectroscopy, and single-crystal X-ray diffraction. The structural analyses confirmed distorted square-planar Pd(II) geometries featuring N,S-bidentate thiosemicarbazide and chelating bisphosphine ligands. The cytotoxicity of the complexes was evaluated against breast (MCF-7 and MDA-MB-231), prostate (DU-145), lung (A549), ovarian (A2780 and A2780cis), and non-tumor (MRC-5) cell lines using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. One of the complexes exhibited the highest cytotoxicity, with IC₅₀ values approaching 1 μM in ovarian and breast cancer cells. B3 was about 25–30 times more active and selective than cisplatin (SI ≈ 15). Additional tests demonstrated that B3 blocked colony formation and migration, triggered dose-dependent apoptosis, and exhibited minimal toxicity to non-tumor cells. Notably, B3 demonstrated significant activity against cisplatin-resistant ovarian cells (A2780cis) in three-dimensional (3D) spheroid cultures, indicating its potential under physiologically relevant conditions. Overall, the structural features represent a promising lead compound for developing next-generation palladium-based metallodrugs with improved selectivity and effectiveness against resistant tumor types.
{"title":"Synthesis, structural characterization, and antitumor evaluation of Pd(II) Thiosemicarbazide–Diphosphine complexes in 2D and 3D cancer models","authors":"Dario B. Fortaleza , Josias S. Rocha , George B.S. Pereira , Tamara Teixeira , Jocely L. Dutra , Carlos A.F. Moraes , Pedro H.O. Santiago , Alzir A. Batista , Moacir R. Forim , Javier A. Ellena , Fillipe V. Rocha","doi":"10.1016/j.jinorgbio.2026.113234","DOIUrl":"10.1016/j.jinorgbio.2026.113234","url":null,"abstract":"<div><div>Cancer remains one of the leading causes of death worldwide, with millions of new cases diagnosed annually. Cisplatin is a major advance in chemotherapy, but its severe side effects and the development of resistance limit its long-term effectiveness. In this context, palladium(II) complexes have gained attention as structural analogues of platinum compounds because they have the potential to exhibit antitumor activity while reducing toxicity. Six novel palladium(II) complexes containing thiosemicarbazide derivatives and diphosphine ligands [1,3-bis(diphenylphosphine)propane (dppp) or 1,4-bis(diphenylphosphine)butane (dppb)] were synthesized and thoroughly characterized by FTIR, <sup>1</sup>H NMR and <sup>31</sup>P NMR, high-resolution mass spectrometry, UV–Vis spectroscopy, and single-crystal X-ray diffraction. The structural analyses confirmed distorted square-planar Pd(II) geometries featuring N,S-bidentate thiosemicarbazide and chelating bisphosphine ligands. The cytotoxicity of the complexes was evaluated against breast (MCF-7 and MDA-MB-231), prostate (DU-145), lung (A549), ovarian (A2780 and A2780cis), and non-tumor (MRC-5) cell lines using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. One of the complexes exhibited the highest cytotoxicity, with IC₅₀ values approaching 1 μM in ovarian and breast cancer cells. B3 was about 25–30 times more active and selective than cisplatin (SI ≈ 15). Additional tests demonstrated that B3 blocked colony formation and migration, triggered dose-dependent apoptosis, and exhibited minimal toxicity to non-tumor cells. Notably, B3 demonstrated significant activity against cisplatin-resistant ovarian cells (A2780cis) in three-dimensional (3D) spheroid cultures, indicating its potential under physiologically relevant conditions. Overall, the structural features represent a promising lead compound for developing next-generation palladium-based metallodrugs with improved selectivity and effectiveness against resistant tumor types.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113234"},"PeriodicalIF":3.2,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037418","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 : 2026-01-19DOI: 10.1016/j.jinorgbio.2026.113240
Petr V. Ostroverkhov , Anna D. Plutinskaya , Ksenia V. Luneva , Evgeniya O. Borzhitskaya , Polina E. Lavrinova , Nikolay D. Govorov , Aleksey B. Golovanov , Ekaterina S. Neryabova , Leonid Y. Martinov , Maxim N. Usachev , Elena V. Filonenko , Olga A. Bezborodova , Mikhail A. Grin
The combination of multiple therapeutic methods or drugs in the treatment of oncological diseases is a well-established strategy commonly referred to as combination therapy. This approach allows to reduce the adverse effects and enhance treatment efficacy by overcoming resistance to one of the agents within the combination. In the present study, novel Pt(II) complexes of natural chlorins bearing carboxyl and pyridine substituents were synthesized as potential agents for combination therapy. The structures of the synthesized complexes were confirmed by various physicochemical methods, including 1H and 13C NMR spectroscopy, mass spectrometry, high-resolution chromatography-mass spectrometry and Fourier-transform infrared (FTIR) spectroscopy. In vitro evaluation of the compounds demonstrated an increase in both photoinduced and dark cytotoxicity of the Pt complexes.
{"title":"Synthesis and evaluation of the combined chemotherapeutic and photodynamic action of new Pt-complexes of natural chlorins","authors":"Petr V. Ostroverkhov , Anna D. Plutinskaya , Ksenia V. Luneva , Evgeniya O. Borzhitskaya , Polina E. Lavrinova , Nikolay D. Govorov , Aleksey B. Golovanov , Ekaterina S. Neryabova , Leonid Y. Martinov , Maxim N. Usachev , Elena V. Filonenko , Olga A. Bezborodova , Mikhail A. Grin","doi":"10.1016/j.jinorgbio.2026.113240","DOIUrl":"10.1016/j.jinorgbio.2026.113240","url":null,"abstract":"<div><div>The combination of multiple therapeutic methods or drugs in the treatment of oncological diseases is a well-established strategy commonly referred to as combination therapy. This approach allows to reduce the adverse effects and enhance treatment efficacy by overcoming resistance to one of the agents within the combination. In the present study, novel Pt(II) complexes of natural chlorins bearing carboxyl and pyridine substituents were synthesized as potential agents for combination therapy. The structures of the synthesized complexes were confirmed by various physicochemical methods, including <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy, mass spectrometry, high-resolution chromatography-mass spectrometry and Fourier-transform infrared (FTIR) spectroscopy. <em>In vitro</em> evaluation of the compounds demonstrated an increase in both photoinduced and dark cytotoxicity of the Pt complexes.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113240"},"PeriodicalIF":3.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023365","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 : 2026-01-17DOI: 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":"2026-01-17","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}
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