Pub Date : 2025-11-10DOI: 10.1016/j.jinorgbio.2025.113148
Wanqing Zhang, Mengyue Tan, Meihua Chen, Weibin Chen, Mei-Jin Li
Cyclometallated Ir(III) complex is a potential photosensitizer for photodynamic therapy (PDT) due to its unique photophysical properties. As an emerging anti-tumor therapy, PDT kills tumor cells by leveraging the toxic reactive oxygen species (ROS) generated by light-activated photosensitizers. In this work, two Ir(III) complexes with aggregation-induced emission (AIE) properties were designed and synthesized. A biosensor based on bovine serum albumin (BSA)-enhanced AIE of Ir(III) complexes for selective sensing of trypsin was constructed and explored. The therapeutic potential of the probes for PDT was evaluated by measuring their ROS generation efficiency, along with their phototoxicity and dark cytotoxicity in HeLa cells. In addition, localization of the two probes on organelles was investigated and the mechanism of apoptosis induced by the probe Ir-2 as a photosensitizer was studied using flow cytometry. The results demonstrated that these AIE-active complexes exhibited high ROS efficiency and good mitochondrial/lysosome dual-organelle targeting capability, which can enhance the efficacy of PDT in cancer treatment. This Ir(III)-AIE theragnostic probe merges enzymatic sensing with organelle-specific PDT, offering dual biomedical applications.
{"title":"Dual-functional AIE-active Ir(III) complexes for trypsin detection and organelle-targeted photodynamic therapy","authors":"Wanqing Zhang, Mengyue Tan, Meihua Chen, Weibin Chen, Mei-Jin Li","doi":"10.1016/j.jinorgbio.2025.113148","DOIUrl":"10.1016/j.jinorgbio.2025.113148","url":null,"abstract":"<div><div>Cyclometallated Ir(III) complex is a potential photosensitizer for photodynamic therapy (PDT) due to its unique photophysical properties. As an emerging anti-tumor therapy, PDT kills tumor cells by leveraging the toxic reactive oxygen species (ROS) generated by light-activated photosensitizers. In this work, two Ir(III) complexes with aggregation-induced emission (AIE) properties were designed and synthesized. A biosensor based on bovine serum albumin (BSA)-enhanced AIE of Ir(III) complexes for selective sensing of trypsin was constructed and explored. The therapeutic potential of the probes for PDT was evaluated by measuring their ROS generation efficiency, along with their phototoxicity and dark cytotoxicity in HeLa cells. In addition, localization of the two probes on organelles was investigated and the mechanism of apoptosis induced by the probe Ir-2 as a photosensitizer was studied using flow cytometry. The results demonstrated that these AIE-active complexes exhibited high ROS efficiency and good mitochondrial/lysosome dual-organelle targeting capability, which can enhance the efficacy of PDT in cancer treatment. This Ir(III)-AIE theragnostic probe merges enzymatic sensing with organelle-specific PDT, offering dual biomedical applications.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113148"},"PeriodicalIF":3.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517437","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 : 2025-11-10DOI: 10.1016/j.jinorgbio.2025.113150
Anthony J. Chavez , Peter C. Ford , Nadia G. Léonard , Mahdi M. Abu-Omar
Mixed-valence multi-metallic complexes, in which the metal is present in more than one oxidation state, provide crucial insight into how electron transfer operates in both biological proteins/enzymes and synthetic inorganic compounds. Nature offers striking examples, such as the oxygen-evolving complex (OEC) of photosystem II, where mixed valency plays an essential role in facilitating proton-coupled electron transfer (PCET) The degree of electronic delocalization between redox sites is subdivided into three groups (Class I, Class II, and Class III) by the Robin-Day classification. Elucidating electronic structure and the function of such systems serves as a foundation for the design of bioinspired catalysts. Nickel, with its rich redox flexibility, is well positioned to form mixed-valent binuclear complexes across several oxidation states, including Ni₂(I,0), Ni₂(I,II), and Ni₂(II,III) dinuclear complexes. Several such systems mirror the redox profiles of enzymes like acetyl-CoA synthase, which is central to C1 metabolism. This perspective highlights the emerging landscape of multinuclear nickel complexes, focusing on their structural classification and redox behavior. Special attention is given to a newly characterized family of Class III Ni₂(I,II) complexes, which exhibit fully delocalized valency. Collectively, this work underscores how mixed-valent states not only advance our understanding of electron transfer mechanisms but can also guide the development of new redox-active materials for catalysis.
{"title":"Mixed-valency in multinuclear nickel complexes: From fundamentals to nickel enzymes","authors":"Anthony J. Chavez , Peter C. Ford , Nadia G. Léonard , Mahdi M. Abu-Omar","doi":"10.1016/j.jinorgbio.2025.113150","DOIUrl":"10.1016/j.jinorgbio.2025.113150","url":null,"abstract":"<div><div>Mixed-valence multi-metallic complexes, in which the metal is present in more than one oxidation state, provide crucial insight into how electron transfer operates in both biological proteins/enzymes and synthetic inorganic compounds. Nature offers striking examples, such as the oxygen-evolving complex (OEC) of photosystem II, where mixed valency plays an essential role in facilitating proton-coupled electron transfer (PCET) The degree of electronic delocalization between redox sites is subdivided into three groups (Class I, Class II, and Class III) by the Robin-Day classification. Elucidating electronic structure and the function of such systems serves as a foundation for the design of bioinspired catalysts. Nickel, with its rich redox flexibility, is well positioned to form mixed-valent binuclear complexes across several oxidation states, including Ni₂(I,0), Ni₂(I,II), and Ni₂(II,III) dinuclear complexes. Several such systems mirror the redox profiles of enzymes like acetyl-CoA synthase, which is central to C1 metabolism. This perspective highlights the emerging landscape of multinuclear nickel complexes, focusing on their structural classification and redox behavior. Special attention is given to a newly characterized family of Class III Ni₂(I,II) complexes, which exhibit fully delocalized valency. Collectively, this work underscores how mixed-valent states not only advance our understanding of electron transfer mechanisms but can also guide the development of new redox-active materials for catalysis.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113150"},"PeriodicalIF":3.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517374","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 : 2025-11-10DOI: 10.1016/j.jinorgbio.2025.113149
Qinglin Chen, Hong Zeng, Jie Wu, Yuanyan Li, Yibao Li, Yongquan Wu
As a photochemical-based treatment approach, photodynamic therapy (PDT) relies on a photosensitiser (PS) that produces reactive oxygen species (ROS) after irradiation, which lead to irreparable cell damage and hence cell death. Cyclometalated iridium(III) complexes are often used in the development of PSs attributed to their rich photophysical properties with high quantum yields, large Stokes shifts, long-lived phosphorescence and good photostability. In addition, phenothiazine has excellent electron-donating ability and good rigid structure, its derivatives have been shown to possess activity against bacteria, malignant cells, and protozoa. In this work, we designed and synthesized two iridium(III) complexes DF-Ir-CHO and DF-Ir-PTZ. The DF-Ir-PTZ contains a novel ligand functionalized with phenothiazine. DF-Ir-PTZ has a better singlet oxygen (1O2) production quantum yield of 0.357 upon light irradiation and negligible dark cytotoxicity, suggesting that its biological safety is favorable. In addition, DF-Ir-PTZ was able to generate 1O2 and ROS in cancer cells under light conditions, leading to cell apoptosis of MCF-7.
{"title":"Exploring the singlet oxygen generation of iridium(III) complex containing phenothiazine for photodynamic therapy","authors":"Qinglin Chen, Hong Zeng, Jie Wu, Yuanyan Li, Yibao Li, Yongquan Wu","doi":"10.1016/j.jinorgbio.2025.113149","DOIUrl":"10.1016/j.jinorgbio.2025.113149","url":null,"abstract":"<div><div>As a photochemical-based treatment approach, photodynamic therapy (PDT) relies on a photosensitiser (PS) that produces reactive oxygen species (ROS) after irradiation, which lead to irreparable cell damage and hence cell death. Cyclometalated iridium(III) complexes are often used in the development of PSs attributed to their rich photophysical properties with high quantum yields, large Stokes shifts, long-lived phosphorescence and good photostability. In addition, phenothiazine has excellent electron-donating ability and good rigid structure, its derivatives have been shown to possess activity against bacteria, malignant cells, and protozoa. In this work, we designed and synthesized two iridium(III) complexes DF-Ir-CHO and DF-Ir-PTZ. The DF-Ir-PTZ contains a novel ligand functionalized with phenothiazine. DF-Ir-PTZ has a better singlet oxygen (<sup>1</sup>O<sub>2</sub>) production quantum yield of 0.357 upon light irradiation and negligible dark cytotoxicity, suggesting that its biological safety is favorable. In addition, DF-Ir-PTZ was able to generate <sup>1</sup>O<sub>2</sub> and ROS in cancer cells under light conditions, leading to cell apoptosis of MCF-7.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113149"},"PeriodicalIF":3.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517438","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 : 2025-11-08DOI: 10.1016/j.jinorgbio.2025.113137
Milica G. Paunović , Miloš M. Matić , Ana D. Obradović , Vesna D. Stanković , Verica V. Jevtić , Branka I. Ognjanović
Due to cisplatin's limited efficacy and adverse effects on healthy tissues, particularly the kidneys, its use is restricted. The objective of this research was to investigate the impact of new Pt(IV) complexes that contain ethyl- propyl- and butyl-esters of the ethylenediamine-N,N′-di-S,S-(2,2′-dibenzyl) acetic acid, as well as possible advantages of resveratrol co-treatment, on the kidneys of female Wistar albino rats by detecting kidney injury markers, oxidative stress parameters and morphological tissue changes. The rats, divided into ten groups, received a single intraperitoneal dosage of cisplatin (7.5 mg/kg) or Pt(IV) complexes (10 mg/kg), and/or resveratrol (25 mg/kg), whereas the control animals received only an ip injection of saline. Acute complexes treatments increased Chl value while decreasing Gl, Cre, and Urea levels, suggesting kidney injury. Novel compounds considerably decreased the levels of O2•−, H2O2 and GSSG, while raising the levels of NO2−, LPO and GSH. In addition, the activities of SOD, GSH-Px, and GST were increased, while the activities of CAT and GR were alleviated. Regarding morphological changes in kidney tissue, they were mostly of mild intensity. Results indicate that used complexes might trigger an imbalance of redox equilibrium of kidney cells and that the renal tissue was more vulnerable to the negative effects of Pt(IV) complexes than to cisplatin. Resveratrol's nephroprotective benefits were not shown. Additionally, a prooxidative effect was registered after co-treatments. These findings could be useful for future studies in clarifying how the investigated compounds act in the estradiol-rich environment and how they affect the tissues of male rats.
{"title":"Assessment of the novel platinum(IV) complexes effects on female rats' kidneys: Possible nephroprotection of resveratrol","authors":"Milica G. Paunović , Miloš M. Matić , Ana D. Obradović , Vesna D. Stanković , Verica V. Jevtić , Branka I. Ognjanović","doi":"10.1016/j.jinorgbio.2025.113137","DOIUrl":"10.1016/j.jinorgbio.2025.113137","url":null,"abstract":"<div><div>Due to cisplatin's limited efficacy and adverse effects on healthy tissues, particularly the kidneys, its use is restricted. The objective of this research was to investigate the impact of new Pt(IV) complexes that contain ethyl- propyl- and butyl-esters of the ethylenediamine-<em>N,N′</em>-di-<em>S,S</em>-(2,2′-dibenzyl) acetic acid, as well as possible advantages of resveratrol co-treatment, on the kidneys of female Wistar albino rats by detecting kidney injury markers, oxidative stress parameters and morphological tissue changes. The rats, divided into ten groups, received a single intraperitoneal dosage of cisplatin (7.5 mg/kg) or Pt(IV) complexes (10 mg/kg), and/or resveratrol (25 mg/kg), whereas the control animals received only an ip injection of saline. Acute complexes treatments increased Chl value while decreasing Gl, Cre, and Urea levels, suggesting kidney injury. Novel compounds considerably decreased the levels of O<sub>2</sub><sup>•−</sup>, H<sub>2</sub>O<sub>2</sub> and GSSG, while raising the levels of NO<sub>2</sub><sup>−</sup>, LPO and GSH. In addition, the activities of SOD, GSH-Px, and GST were increased, while the activities of CAT and GR were alleviated. Regarding morphological changes in kidney tissue, they were mostly of mild intensity. Results indicate that used complexes might trigger an imbalance of redox equilibrium of kidney cells and that the renal tissue was more vulnerable to the negative effects of Pt(IV) complexes than to cisplatin. Resveratrol's nephroprotective benefits were not shown. Additionally, a prooxidative effect was registered after co-treatments. These findings could be useful for future studies in clarifying how the investigated compounds act in the estradiol-rich environment and how they affect the tissues of male rats.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113137"},"PeriodicalIF":3.2,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517373","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 : 2025-11-08DOI: 10.1016/j.jinorgbio.2025.113142
Camila Aparecida da Silva dos Reis Condé , Katherine Lima Bruno , Camilla Barbosa Calçado , Giset Y. Sánchez Delgado , Willian Xerxes Coelho Oliveira , Heveline Silva , Maribel Navarro
According to the World Health Organization, an estimated 9.7 million people died from cancer worldwide in 2024. Considering this devastating scenario, our strategy is to search for gold(I) compounds with the potential to be used as anticancer drugs. We have synthesized the organometallic gold(I)-NHC methylclotrimazole (CTZMe, 1) and gold(I)-NHC methylketoconazole (KTZMe, 2), as well as the gold(I)-CTZ (clotrimazole)/KTZ (ketoconazole) coordination compounds (3–4). Their structures were confirmed through full characterization using analytical and spectroscopic techniques including elemental analysis, molar conductivity, infrared (IR), ultraviolet–visible (UV–Vis), magnetic nuclear resonance (NMR), electrospray ionization mass spectrometry (ESI–MS), and X-ray diffraction of a single crystal for complex 1, with additional support from theoretical calculations. Gold(I) complexes (1–4) were tested against tumor cell lines (MDA-MB-231 and 4 T1) and in a normal cell line (MCF-10 A), revealing that complexes 1–4 were generally more active and selective than free imidazole antifungal drugs and their imidazolium salts, with compound 1 being the most active. These gold complexes (1–4) were found to interact with DNA; however, this was not the main target. Instead, they displayed substantial interaction with glutathione, as determined by colorimetric assay and NMR-monitored analysis, suggesting preferential interaction with thiol-containing enzymes such as Thioredoxin Reductase (TrxR). Molecular docking suggested two possible modes of TrxR inhibition: (i) redox-center blockade by KTZ-containing compounds (2 and 4) and (ii) direct AuS binding by CTZ-based compounds (1 and 3), particularly for the most active complex 1, which might contribute to its higher anticancer activity.
{"title":"Organometallic and coordination gold(I)-azole drugs compounds: Synthesis, characterization, antitumor evaluation, and interactions with biomolecules","authors":"Camila Aparecida da Silva dos Reis Condé , Katherine Lima Bruno , Camilla Barbosa Calçado , Giset Y. Sánchez Delgado , Willian Xerxes Coelho Oliveira , Heveline Silva , Maribel Navarro","doi":"10.1016/j.jinorgbio.2025.113142","DOIUrl":"10.1016/j.jinorgbio.2025.113142","url":null,"abstract":"<div><div>According to the World Health Organization, an estimated 9.7 million people died from cancer worldwide in 2024. Considering this devastating scenario, our strategy is to search for gold(I) compounds with the potential to be used as anticancer drugs. We have synthesized the organometallic gold(I)-NHC methylclotrimazole (CTZMe, <strong>1</strong>) and gold(I)-NHC methylketoconazole (KTZMe, <strong>2</strong>), as well as the gold(I)-CTZ (clotrimazole)/KTZ (ketoconazole) coordination compounds (<strong>3</strong>–<strong>4</strong>). Their structures were confirmed through full characterization using analytical and spectroscopic techniques including elemental analysis, molar conductivity, infrared (IR), ultraviolet–visible (UV–Vis), magnetic nuclear resonance (NMR), electrospray ionization mass spectrometry (ESI–MS), and X-ray diffraction of a single crystal for complex <strong>1</strong>, with additional support from theoretical calculations. Gold(I) complexes (<strong>1</strong>–<strong>4</strong>) were tested against tumor cell lines (MDA-MB-231 and 4 T1) and in a normal cell line (MCF-10 A), revealing that complexes <strong>1</strong>–<strong>4</strong> were generally more active and selective than free imidazole antifungal drugs and their imidazolium salts, with compound <strong>1</strong> being the most active. These gold complexes (<strong>1</strong>–<strong>4</strong>) were found to interact with DNA; however, this was not the main target. Instead, they displayed substantial interaction with glutathione, as determined by colorimetric assay and NMR-monitored analysis, suggesting preferential interaction with thiol-containing enzymes such as Thioredoxin Reductase (TrxR). Molecular docking suggested two possible modes of TrxR inhibition: (i) redox-center blockade by KTZ-containing compounds (<strong>2</strong> and <strong>4</strong>) and (ii) direct Au<img>S binding by CTZ-based compounds (<strong>1</strong> and <strong>3</strong>), particularly for the most active complex <strong>1</strong>, which might contribute to its higher anticancer activity.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113142"},"PeriodicalIF":3.2,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517372","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 : 2025-11-08DOI: 10.1016/j.jinorgbio.2025.113141
Jane Fu , Nejc Nagelj , Matthew C. Drummer , Kristopher G. Reynolds , Dave Y. Song , JoAnne Stubbe , Daniel G. Nocera
Tryptophan radicals are relevant to charge transport and catalysis in several enzymes. The radical is produced by the removal of an electron and proton from tryptophan. Despite its prevalence, tools to probe tryptophan radicals in biological systems remain limited. Fluorination of the indole ring of tryptophan induces changes in the redox potential, pKa and absorption spectrum, thus making fluorotryptophans attractive residues to probe the transient role of tryptophan radicals in biological systems. A series of N-acylated mono-fluorotryptophan amide analogs have been synthesized. Fluorine substitution at the 4 to 7 positions on the indole ring expands the a pKa of the indole proton from 4.6 to 3.8–4.0 and a shift in reduction potential of 70 to 115 mV in the pH independent region (pH < 4) and 33 to 72 mV in the pH dependent regime that is accessible to most proteins (pH 6 to 9). Spectral shifts between 550 and 620 nm for the fluorotryptophan radical cation and between 495 and 550 nm for the neutral fluorotryptophan radical, respectively, allow their transient formation to be differentiated from background tryptophans in protein systems. The red shift of the radical cation as compared to the neutral radical is captured by DFT calculations and is shown to arise primarily from the stabilization of the radical cation SOMO. With the emergence of genetic code expansion techniques for incorporating fluorotryptophans in proteins, the mono-fluorotryptophans reported herein will be useful unnatural amino acids for examining tryptophan radicals in biology.
{"title":"Mono-fluorotryptophans as probes of proton-coupled electron transfer in biology","authors":"Jane Fu , Nejc Nagelj , Matthew C. Drummer , Kristopher G. Reynolds , Dave Y. Song , JoAnne Stubbe , Daniel G. Nocera","doi":"10.1016/j.jinorgbio.2025.113141","DOIUrl":"10.1016/j.jinorgbio.2025.113141","url":null,"abstract":"<div><div>Tryptophan radicals are relevant to charge transport and catalysis in several enzymes. The radical is produced by the removal of an electron and proton from tryptophan. Despite its prevalence, tools to probe tryptophan radicals in biological systems remain limited. Fluorination of the indole ring of tryptophan induces changes in the redox potential, p<em>K</em><sub>a</sub> and absorption spectrum, thus making fluorotryptophans attractive residues to probe the transient role of tryptophan radicals in biological systems. A series of N-acylated mono-fluorotryptophan amide analogs have been synthesized. Fluorine substitution at the 4 to 7 positions on the indole ring expands the a p<em>K</em><sub>a</sub> of the indole proton from 4.6 to 3.8–4.0 and a shift in reduction potential of 70 to 115 mV in the pH independent region (pH < 4) and 33 to 72 mV in the pH dependent regime that is accessible to most proteins (pH 6 to 9). Spectral shifts between 550 and 620 nm for the fluorotryptophan radical cation and between 495 and 550 nm for the neutral fluorotryptophan radical, respectively, allow their transient formation to be differentiated from background tryptophans in protein systems. The red shift of the radical cation as compared to the neutral radical is captured by DFT calculations and is shown to arise primarily from the stabilization of the radical cation SOMO. With the emergence of genetic code expansion techniques for incorporating fluorotryptophans in proteins, the mono-fluorotryptophans reported herein will be useful unnatural amino acids for examining tryptophan radicals in biology.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113141"},"PeriodicalIF":3.2,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534065","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 : 2025-11-07DOI: 10.1016/j.jinorgbio.2025.113145
Haipei Zou , Samantha N. MacMillan , Justin J. Wilson
Ru265, [Ru2(μ-N)(NH3)8Cl2]Cl3, is a potent nanomolar inhibitor of the mitochondrial calcium uniporter (MCU), the transporter that mediates Ca2+ uptake into the mitochondria. This compound and related MCU inhibitors are promising therapeutic agents and chemical biology tools for studying intracellular Ca2+ dynamics. Axial ligand modification of these Ru-based complexes provides a facile way to tune their properties and make prodrugs. In this study, the use of axial phosphonate and phosphinate ligands was explored within this compound class, yielding [Ru2(μ-N)(NH3)8(OPO(OH)Me)2](CF3SO3)3 (1) and [Ru2(μ-N)(NH3)8(OPOPh2)2](CF3SO3)3 (2). Both complexes were characterized by multinuclear NMR spectroscopy, revealing downfield shifts of the 31P resonances of the coordinated ligands. The crystal structure of 1 was also obtained, which confirmed coordination of the methylphosphonate ligands to the axial sites of the Ru core. The aquation of 1 and 2 were studied by NMR and UV–vis spectroscopy. Unexpectedly, compound 1 undergoes partial aquation, arresting at a final product in which only one axial methylphosphonate is displaced by water. By contrast, 2 loses both diphenylphosphinates via aquation (t1/2 = 1.7 h) under physiological conditions. The in vitro biological investigations of 1 and 2 in HeLa cells showed that neither demonstrate high cytotoxicity nor depolarize the mitochondrial membrane potential. Both compounds exhibit nanomolar inhibitory activity against mitochondrial Ca2+ uptake in permeabilized HEK293T cells and modest inhibitory activity against this process in intact HeLa cells. Notably, 1 shows pH-dependent activity for MCU inhibition, with greater inhibition in more acidic conditions, while 2 shows improvement in cellular uptake efficiency.
{"title":"Employing phosphonate and phosphinate ligands for prodrug development of the mitochondrial calcium uniporter inhibitor Ru265","authors":"Haipei Zou , Samantha N. MacMillan , Justin J. Wilson","doi":"10.1016/j.jinorgbio.2025.113145","DOIUrl":"10.1016/j.jinorgbio.2025.113145","url":null,"abstract":"<div><div>Ru265, [Ru<sub>2</sub>(μ-N)(NH<sub>3</sub>)<sub>8</sub>Cl<sub>2</sub>]Cl<sub>3</sub>, is a potent nanomolar inhibitor of the mitochondrial calcium uniporter (MCU), the transporter that mediates Ca<sup>2+</sup> uptake into the mitochondria. This compound and related MCU inhibitors are promising therapeutic agents and chemical biology tools for studying intracellular Ca<sup>2+</sup> dynamics. Axial ligand modification of these Ru-based complexes provides a facile way to tune their properties and make prodrugs. In this study, the use of axial phosphonate and phosphinate ligands was explored within this compound class, yielding [Ru<sub>2</sub>(μ-N)(NH<sub>3</sub>)<sub>8</sub>(OPO(OH)Me)<sub>2</sub>](CF<sub>3</sub>SO<sub>3</sub>)<sub>3</sub> (<strong>1</strong>) and [Ru<sub>2</sub>(μ-N)(NH<sub>3</sub>)<sub>8</sub>(OPOPh<sub>2</sub>)<sub>2</sub>](CF<sub>3</sub>SO<sub>3</sub>)<sub>3</sub> (<strong>2</strong>). Both complexes were characterized by multinuclear NMR spectroscopy, revealing downfield shifts of the <sup>31</sup>P resonances of the coordinated ligands. The crystal structure of <strong>1</strong> was also obtained, which confirmed coordination of the methylphosphonate ligands to the axial sites of the Ru core. The aquation of <strong>1</strong> and <strong>2</strong> were studied by NMR and UV–vis spectroscopy. Unexpectedly, compound <strong>1</strong> undergoes partial aquation, arresting at a final product in which only one axial methylphosphonate is displaced by water. By contrast, <strong>2</strong> loses both diphenylphosphinates via aquation (t<sub>1/2</sub> = 1.7 h) under physiological conditions. The in vitro biological investigations of <strong>1</strong> and <strong>2</strong> in HeLa cells showed that neither demonstrate high cytotoxicity nor depolarize the mitochondrial membrane potential. Both compounds exhibit nanomolar inhibitory activity against mitochondrial Ca<sup>2+</sup> uptake in permeabilized HEK293T cells and modest inhibitory activity against this process in intact HeLa cells. Notably, <strong>1</strong> shows pH-dependent activity for MCU inhibition, with greater inhibition in more acidic conditions, while <strong>2</strong> shows improvement in cellular uptake efficiency.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113145"},"PeriodicalIF":3.2,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562227","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 : 2025-11-07DOI: 10.1016/j.jinorgbio.2025.113140
Anna Poznańska , Przemysław Gajda-Morszewski , Ilona Gurgul , Olga Mazuryk , Justyna Kalinowska-Tłuścik , Małgorzata Brindell
The concentration of free drug available for target binding is significantly influenced by its interaction with plasma proteins, primarily human serum albumin (HSA). In this study, we focused on the interactions between HSA and polypyridyl ruthenium complexes, a class of compounds known for their cytotoxic and antimetastatic properties. Since the fluorescence quenching technique for determining dissociation constants was not applicable in the studied case, a novel TRIC (temperature-related intensity change) technique was employed in combination with molecular docking to gain a deeper understanding of mutual recognition and binding. To assess the biological relevance of these interactions, we also conducted in vitro experiments, evaluating cytotoxicity and cellular uptake. Our findings revealed moderate binding (dissociation constant ranging from 0.2 to 1.2 mM) of the ruthenium complexes to HSA, resulting in a low protein-bound fraction. The result was consistent with the negligible impact of HSA observed on cytotoxicity and cellular uptake in human breast cancer MCF-7 cells. The integration of TRIC with molecular docking provided a valuable insight into metal complex-protein interaction and demonstrated a powerful strategy in medicinal chemistry, enabling the rational modulation of drug-protein interactions to optimize the pharmacokinetics of metal-based therapeutics.
{"title":"Biophysical and in silico studies on the interaction of polypyridyl ruthenium complexes with human serum albumin: Overcoming low affinity and high luminescence challenges","authors":"Anna Poznańska , Przemysław Gajda-Morszewski , Ilona Gurgul , Olga Mazuryk , Justyna Kalinowska-Tłuścik , Małgorzata Brindell","doi":"10.1016/j.jinorgbio.2025.113140","DOIUrl":"10.1016/j.jinorgbio.2025.113140","url":null,"abstract":"<div><div>The concentration of free drug available for target binding is significantly influenced by its interaction with plasma proteins, primarily human serum albumin (HSA). In this study, we focused on the interactions between HSA and polypyridyl ruthenium complexes, a class of compounds known for their cytotoxic and antimetastatic properties. Since the fluorescence quenching technique for determining dissociation constants was not applicable in the studied case, a novel TRIC (temperature-related intensity change) technique was employed in combination with molecular docking to gain a deeper understanding of mutual recognition and binding. To assess the biological relevance of these interactions, we also conducted <em>in vitro</em> experiments, evaluating cytotoxicity and cellular uptake. Our findings revealed moderate binding (dissociation constant ranging from 0.2 to 1.2 mM) of the ruthenium complexes to HSA, resulting in a low protein-bound fraction. The result was consistent with the negligible impact of HSA observed on cytotoxicity and cellular uptake in human breast cancer MCF-7 cells. The integration of TRIC with molecular docking provided a valuable insight into metal complex-protein interaction and demonstrated a powerful strategy in medicinal chemistry, enabling the rational modulation of drug-protein interactions to optimize the pharmacokinetics of metal-based therapeutics.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113140"},"PeriodicalIF":3.2,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501339","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 : 2025-11-07DOI: 10.1016/j.jinorgbio.2025.113136
Edward I. Solomon , Robert R. Gipson
{"title":"Corrigendum to ‘Activating metal sites for electron transfer and catalysis’ [Journal of Inorganic Biochemistry vol 272 (2025) 113009]","authors":"Edward I. Solomon , Robert R. Gipson","doi":"10.1016/j.jinorgbio.2025.113136","DOIUrl":"10.1016/j.jinorgbio.2025.113136","url":null,"abstract":"","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113136"},"PeriodicalIF":3.2,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530325","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 : 2025-11-07DOI: 10.1016/j.jinorgbio.2025.113147
Kylie S. Uyeda, A.S. Borovik
The evolution of oxidative metabolism has shaped life on Earth, from ancient anaerobic microorganisms to modern eukaryotes. Central to aerobic life is the ability of metalloproteins to regulate and utilize dioxygen through tightly controlled biochemical processes. Beginning with the emergence of oxygenic photosynthesis and aerobic respiration, the pivotal roles of metalloenzymes in dioxygen activation, utilization and detoxification are then highlighted. Bridging perspectives from bioinorganic chemistry, enzymology, synthetic biology and microbiome science, we discuss how studies of biomimetic molecular complexes and natural and artificial metalloproteins illuminate the structural and functional strategies used to manage dioxygen reactivity. We further consider the systemic roles of metal ions in maintaining redox balance, shaping host-microbe interactions, and contributing to pathological outcomes when misregulated. A foundation is established for understanding the critical roles that metal ions play in dioxygen chemistry that underpins both healthy metabolism and oxidative stress related diseases.
{"title":"Forged in O2: Transition metal ions and the rise of aerobic life","authors":"Kylie S. Uyeda, A.S. Borovik","doi":"10.1016/j.jinorgbio.2025.113147","DOIUrl":"10.1016/j.jinorgbio.2025.113147","url":null,"abstract":"<div><div>The evolution of oxidative metabolism has shaped life on Earth, from ancient anaerobic microorganisms to modern eukaryotes. Central to aerobic life is the ability of metalloproteins to regulate and utilize dioxygen through tightly controlled biochemical processes. Beginning with the emergence of oxygenic photosynthesis and aerobic respiration, the pivotal roles of metalloenzymes in dioxygen activation, utilization and detoxification are then highlighted. Bridging perspectives from bioinorganic chemistry, enzymology, synthetic biology and microbiome science, we discuss how studies of biomimetic molecular complexes and natural and artificial metalloproteins illuminate the structural and functional strategies used to manage dioxygen reactivity. We further consider the systemic roles of metal ions in maintaining redox balance, shaping host-microbe interactions, and contributing to pathological outcomes when misregulated. A foundation is established for understanding the critical roles that metal ions play in dioxygen chemistry that underpins both healthy metabolism and oxidative stress related diseases.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113147"},"PeriodicalIF":3.2,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562270","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号