Pub Date : 2025-09-19DOI: 10.1016/j.jinorgbio.2025.113078
Skyler A. Markham , Kendall E. Jenkins , Avery M. Gibson , Craig C. McLauchlan , Debbie C. Crans
Vanadium complexes have many desirable catalytic and biological properties across a wide variety of chelate types with coordination moieties typically being oxygen and nitrogen. In this work, we carried out a data mining analysis investigating the conformation of six-membered rings formed between a ligand and a vanadium atom with the objective to understand how much the ligand conformation impacted the structure and stability of the coordination complex. There are 104 structures with the NVN unit in the Cambridge Crystallographic Data Centre (CCDC), 28 structures with OVN unit, 386 structures with the OVO unit, and 11 structures with NVN(sp2)C(sp2) unit, with the remainder of the six-membered ring being three C atoms. The structures containing NVN, OVN, OVO, and NVN(sp2)C(sp2) units show chelate geometries including chair, twist-boat, boat, and half-chair. Out of the total 529 structures, there were 315 chairs (60 %), 91 twist-boats (17 %), 86 boats (16 %), 4 half-chairs (1 %), 2 planar (0.5 %), 13 complexes that contained more than one 6-membered ring and the complex having more than one chelate conformation (2.5 %), and 16 complexes where the structures are not deposited in the CCDC (3 %). Based on the analysis, there is a distinct correlation between the conformation of the ring and the composition of the chelate of the mononuclear, dinuclear and polyoxidovanadate complexes containing NVN, OVN, OVO and NVN(sp2)C(sp2) groups. Therefore, it appears that the chelate composition impacts the conformation of the six-membered ring and thus the stability of the complex.
{"title":"Conformation of six-membered vanadium chelate rings","authors":"Skyler A. Markham , Kendall E. Jenkins , Avery M. Gibson , Craig C. McLauchlan , Debbie C. Crans","doi":"10.1016/j.jinorgbio.2025.113078","DOIUrl":"10.1016/j.jinorgbio.2025.113078","url":null,"abstract":"<div><div>Vanadium complexes have many desirable catalytic and biological properties across a wide variety of chelate types with coordination moieties typically being oxygen and nitrogen. In this work, we carried out a data mining analysis investigating the conformation of six-membered rings formed between a ligand and a vanadium atom with the objective to understand how much the ligand conformation impacted the structure and stability of the coordination complex. There are 104 structures with the NVN unit in the Cambridge Crystallographic Data Centre (CCDC), 28 structures with OVN unit, 386 structures with the OVO unit, and 11 structures with NVN(sp<sup>2</sup>)C(sp<sup>2</sup>) unit, with the remainder of the six-membered ring being three C atoms. The structures containing NVN, OVN, OVO, and NVN(sp<sup>2</sup>)C(sp<sup>2</sup>) units show chelate geometries including chair, twist-boat, boat, and half-chair. Out of the total 529 structures, there were 315 chairs (60 %), 91 twist-boats (17 %), 86 boats (16 %), 4 half-chairs (1 %), 2 planar (0.5 %), 13 complexes that contained more than one 6-membered ring and the complex having more than one chelate conformation (2.5 %), and 16 complexes where the structures are not deposited in the CCDC (3 %). Based on the analysis, there is a distinct correlation between the conformation of the ring and the composition of the chelate of the mononuclear, dinuclear and polyoxidovanadate complexes containing NVN, OVN, OVO and NVN(sp<sup>2</sup>)C(sp<sup>2</sup>) groups. Therefore, it appears that the chelate composition impacts the conformation of the six-membered ring and thus the stability of the complex.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113078"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205035","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 : 2025-09-19DOI: 10.1016/j.jinorgbio.2025.113081
Massimo Coletta , Gabriele Antonio Zingale , Giovanna De Simone , Giampiero De Sanctis , Virginia Quadrotta , Fabio Polticelli , Paolo Ascenzi
Mini-myoglobin (mini-HH-Mb) is a proteolytic fragment of horse heart myoglobin (HH-Mb) comprising residues 32–139, grossly corresponding to the central exon of the HH-Mb gene, which encodes residues 31–105. Unlike HH-Mb, which displays a single exponential for both CO association and CO dissociation kinetics, mini-HH-Mb shows a biphasic kinetic behavior for both processes, indicating the presence of at least two distinct conformations which are in a very slow (or no) equilibrium with each other. Between pH 2 and 12, CO association to both species of mini-HH-Mb shows two proton-linked transitions, one in the neutral-alkaline pH range (not observed for HH-Mb) and a second one in the acidic region displaying a pKa of 2.9 like that observed in HH-Mb (pKa = 2.7). Kinetics of CO dissociation from both species of mini-HH-Mb-CO was investigated between pH 5.5 and 10.5 only, since outside this pH range the slow CO dissociation kinetics are affected by protein denaturation, which shows up after few seconds. The CO dissociation rate shows a bell-shaped pH dependence for both conformations, while ligand dissociation from HH-Mb-CO is pH-independent. These features find a structural basis on molecular modelling, displaying a higher flexibility of both the proximal and distal side of the heme pocket in mini-HH-Mb, envisaging multiple conformations with different reactivity. This indicates that mini-HH-Mb differs from HH-Mb, suggesting a significant structural-functional role for the N- and C-terminal regions in O2 supply to highly demanding tissues, like the retina, with implications for improving retinal blood flow in ocular pathologies.
{"title":"Horse heart mini- and full length-myoglobin: pH effects on CO binding","authors":"Massimo Coletta , Gabriele Antonio Zingale , Giovanna De Simone , Giampiero De Sanctis , Virginia Quadrotta , Fabio Polticelli , Paolo Ascenzi","doi":"10.1016/j.jinorgbio.2025.113081","DOIUrl":"10.1016/j.jinorgbio.2025.113081","url":null,"abstract":"<div><div>Mini-myoglobin (mini-HH-Mb) is a proteolytic fragment of horse heart myoglobin (HH-Mb) comprising residues 32–139, grossly corresponding to the central exon of the HH-Mb gene, which encodes residues 31–105. Unlike HH-Mb, which displays a single exponential for both CO association and CO dissociation kinetics, mini-HH-Mb shows a biphasic kinetic behavior for both processes, indicating the presence of at least two distinct conformations which are in a very slow (or no) equilibrium with each other. Between pH 2 and 12, CO association to both species of mini-HH-Mb shows two proton-linked transitions, one in the neutral-alkaline pH range (not observed for HH-Mb) and a second one in the acidic region displaying a p<em>K</em><sub>a</sub> of 2.9 like that observed in HH-Mb (p<em>K</em><sub>a</sub> = 2.7). Kinetics of CO dissociation from both species of mini-HH-Mb-CO was investigated between pH 5.5 and 10.5 only, since outside this pH range the slow CO dissociation kinetics are affected by protein denaturation, which shows up after few seconds. The CO dissociation rate shows a bell-shaped pH dependence for both conformations, while ligand dissociation from HH-Mb-CO is pH-independent. These features find a structural basis on molecular modelling, displaying a higher flexibility of both the proximal and distal side of the heme pocket in mini-HH-Mb, envisaging multiple conformations with different reactivity. This indicates that mini-HH-Mb differs from HH-Mb, suggesting a significant structural-functional role for the <em>N</em>- and <em>C</em>-terminal regions in O<sub>2</sub> supply to highly demanding tissues, like the retina, with implications for improving retinal blood flow in ocular pathologies.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113081"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109449","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 : 2025-09-16DOI: 10.1016/j.jinorgbio.2025.113072
Janetsi Y. Caro Ramírez, Patricia A.M. Williams, Evelina G. Ferrer, Luciana G. Naso
Cancer is responsible for about 22.8 % of global deaths from noncommunicable diseases, with lung cancer the most diagnosed in 2022. Non-small cell lung cancer (NSCLC) accounts for 85–90 % of cases. Conventional treatments like chemotherapy have limitations, including low bioavailability and drug resistance. Drug repositioning, where existing medications are used for new purposes, has emerged as a promising approach. This study advances the understanding of antitumor effects of the copper-naringenin (Cu-Nar) complexes: CuNar, CuNarPhen, CuNarBatho [CuNarPhen and CuNarBatho feature CuNar containing phenanthroline (Phen) or bathophenanthroline (Batho)] in lung cancer cells (A549). Clonogenic assays in 2D cultures showed that CuNarBatho was the most effective complex in inhibiting colony formation. Likewise, in a 3D culture model, CuNarBatho disrupted tumor spheroids and demonstrated significant cytotoxicity, with an IC50 value of 11.72 μM. The effect on metastatic processes was also studied, revealing that the complexes significantly reduced cell migration, adhesion, and invasion, particularly CuNarBatho. Zymography assays showed that this complex inhibited the activity of matrix metalloproteinases (MMP-2 and MMP-9), key enzymes involved in cancer metastasis. Additionally, the cytotoxic effects of the three complexes in combination with the antidepressant agent paroxetine, a selective serotonin reuptake inhibitor, were studied, and its inhibitory effect in A549 cells was also determined. When paroxetine and the copper complexes were combined, different degrees of synergy were observed, with CuNarBatho exhibiting the most impactful synergistic effect. These findings suggest that CuNarBatho has potential as a novel therapeutic strategy for lung cancer.
{"title":"Influence of Bathophenanthroline in Cu-Naringenin complexes on 3D culture anticancer activity, antimetastatic properties and synergy with the antidepressant paroxetine","authors":"Janetsi Y. Caro Ramírez, Patricia A.M. Williams, Evelina G. Ferrer, Luciana G. Naso","doi":"10.1016/j.jinorgbio.2025.113072","DOIUrl":"10.1016/j.jinorgbio.2025.113072","url":null,"abstract":"<div><div>Cancer is responsible for about 22.8 % of global deaths from noncommunicable diseases, with lung cancer the most diagnosed in 2022. Non-small cell lung cancer (NSCLC) accounts for 85–90 % of cases. Conventional treatments like chemotherapy have limitations, including low bioavailability and drug resistance. Drug repositioning, where existing medications are used for new purposes, has emerged as a promising approach. This study advances the understanding of antitumor effects of the copper-naringenin (Cu-Nar) complexes: CuNar, CuNarPhen, CuNarBatho [CuNarPhen and CuNarBatho feature CuNar containing phenanthroline (Phen) or bathophenanthroline (Batho)] in lung cancer cells (A549). Clonogenic assays in 2D cultures showed that CuNarBatho was the most effective complex in inhibiting colony formation. Likewise, in a 3D culture model, CuNarBatho disrupted tumor spheroids and demonstrated significant cytotoxicity, with an IC<sub>50</sub> value of 11.72 μM. The effect on metastatic processes was also studied, revealing that the complexes significantly reduced cell migration, adhesion, and invasion, particularly CuNarBatho. Zymography assays showed that this complex inhibited the activity of matrix metalloproteinases (MMP-2 and MMP-9), key enzymes involved in cancer metastasis. Additionally, the cytotoxic effects of the three complexes in combination with the antidepressant agent paroxetine, a selective serotonin reuptake inhibitor, were studied, and its inhibitory effect in A549 cells was also determined. When paroxetine and the copper complexes were combined, different degrees of synergy were observed, with CuNarBatho exhibiting the most impactful synergistic effect. These findings suggest that CuNarBatho has potential as a novel therapeutic strategy for lung cancer.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113072"},"PeriodicalIF":3.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109562","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 : 2025-09-16DOI: 10.1016/j.jinorgbio.2025.113074
Selma Fetahović , Muhamed Fočak , Aleksandar Višnjevac , Sunčica Roca , Višnja Muzika , Dijana Žilić , Lucija Vujević , Sabina Žero , Walter Gössler , Lorenz Steiner , Debbie C. Crans , Adnan Zahirović
Four new heteroleptic neutral paramagnetic mononuclear oxidovanadium(IV) complexes, designated as [VOL(phen)], where L corresponds to acetophenone isoniazid hydrazone or its 5-halogenated derivatives and phen stands for 1,10-phenanthroline, were synthesized and thoroughly characterized using chemical analysis, various spectroscopic techniques, and diffraction methods. Single-crystal X-ray diffraction revealed the molecular and crystal structures of two complexes, showing an octahedral coordination environment around the vanadium(IV) center. The coordination includes a tridentate ONO donor hydrazone ligand in its deprotonated enol-imine form, 1,10-phenanthroline as a bidentate NN donor ternary ligand, and one terminal oxygen atom. The biochemical and hematological effects of these complexes were evaluated in a streptozotocin-induced diabetic rat model. All synthesized complexes showed cholesterol-lowering effects compared to the diabetic rat group, with the vanadium complex lacking a substituent on the acetophenone ring of hydrazone showing the strongest effect. Complexes exhibited comparable and significant antidiabetic activity in vivo, effectively reducing hyperglycemia within 1 week of treatment. Additionally, the histopathological effects of complex (4) on liver, kidney, and brain tissues were investigated. All four complexes were found to have low bioaccumulation levels, with total absolute bioaccumulation in all tested organs less than 0.35% of the administered dose.
{"title":"Vanadium(IV) complexes of acetophenone isoniazid hydrazones: Synthesis, characterization, stability assay, antidiabetic activity, histopathology and bioaccumulation","authors":"Selma Fetahović , Muhamed Fočak , Aleksandar Višnjevac , Sunčica Roca , Višnja Muzika , Dijana Žilić , Lucija Vujević , Sabina Žero , Walter Gössler , Lorenz Steiner , Debbie C. Crans , Adnan Zahirović","doi":"10.1016/j.jinorgbio.2025.113074","DOIUrl":"10.1016/j.jinorgbio.2025.113074","url":null,"abstract":"<div><div>Four new heteroleptic neutral paramagnetic mononuclear oxidovanadium(IV) complexes, designated as [VOL(phen)], where L corresponds to acetophenone isoniazid hydrazone or its 5-halogenated derivatives and phen stands for 1,10-phenanthroline, were synthesized and thoroughly characterized using chemical analysis, various spectroscopic techniques, and diffraction methods. Single-crystal X-ray diffraction revealed the molecular and crystal structures of two complexes, showing an octahedral coordination environment around the vanadium(IV) center. The coordination includes a tridentate ONO donor hydrazone ligand in its deprotonated enol-imine form, 1,10-phenanthroline as a bidentate NN donor ternary ligand, and one terminal oxygen atom. The biochemical and hematological effects of these complexes were evaluated in a streptozotocin-induced diabetic rat model. All synthesized complexes showed cholesterol-lowering effects compared to the diabetic rat group, with the vanadium complex lacking a substituent on the acetophenone ring of hydrazone showing the strongest effect. Complexes exhibited comparable and significant antidiabetic activity <em>in vivo</em>, effectively reducing hyperglycemia within 1 week of treatment. Additionally, the histopathological effects of complex (<strong>4</strong>) on liver, kidney, and brain tissues were investigated. All four complexes were found to have low bioaccumulation levels, with total absolute bioaccumulation in all tested organs less than 0.35% of the administered dose.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113074"},"PeriodicalIF":3.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155122","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 : 2025-09-15DOI: 10.1016/j.jinorgbio.2025.113073
Nouf Alsiraey , Howard D. Dewald
Nitric oxide (NO), an essential inorganic signaling molecule, involved in many physiological processes and has promising therapeutic potential Its oxidation product, peroxynitrite (ONOO¯), is cytotoxic, and elevated ONOO¯ levels induce nitroxidative stress, a factor implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Through pharmacological modulation of NO and ONOO¯ levels in human neural progenitor cell (hNPCs), this study explores the potential pharmaceutical interventions targeting the NO and the neuronal nitric oxide synthase (nNOS) pathway, (NO/nNOS), to prevent or reduce AD progression by restoring the [NO]/[ONOO¯] balance. To achieve this, metalloporphyrin nanosensors have been effectively employed for real-time, in-situ measurement of NO and ONOO¯ concentrations (200–300 nm diameter) were applied and precisely positioned 4–5 ± 1 μm from hNPCs membranes, enabling precise investigation of the [NO]/[ONOO¯] ratio. The [NO]/[ONOO¯] ratio emerged as a critical biomarker for the evaluation of nNOS coupling/uncoupling to the hNPC functioning/dysfunction. In healthy cells, this ratio was around 0.25 ± 0.005, While dysfunctional hNPCs treated to amyloid beta 42 (Aβ42)—a hallmark of AD—caused a dramatic 94 % drop, signaling severe cellular dysfunction. Based on these findings, potential pharmacological interventions have been proposed to prevent or reduce AD progression by restoring the [NO]/[ONOO¯] balance. Notably, a co-treatment of sepiapterin (SEP), a cofactor precursor for NO synthesis, with VAS 2870 (an NADPH oxidase inhibitor) partially restored the ratio to 0.1, indicating improved nNOS function.
{"title":"Restoring nitric oxide/Peroxynitrite equilibrium in impaired human neural progenitor cells: Nanomedical approaches and their potential impact on neurodegenerative disease treatment","authors":"Nouf Alsiraey , Howard D. Dewald","doi":"10.1016/j.jinorgbio.2025.113073","DOIUrl":"10.1016/j.jinorgbio.2025.113073","url":null,"abstract":"<div><div>Nitric oxide (NO), an essential inorganic signaling molecule, involved in many physiological processes and has promising therapeutic potential Its oxidation product, peroxynitrite (ONOO<sup>¯</sup>), is cytotoxic, and elevated ONOO<sup>¯</sup> levels induce nitroxidative stress, a factor implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Through pharmacological modulation of NO and ONOO<sup>¯</sup> levels in human neural progenitor cell (hNPCs), this study explores the potential pharmaceutical interventions targeting the NO and the neuronal nitric oxide synthase (nNOS) pathway, (NO/nNOS), to prevent or reduce AD progression by restoring the [NO]/[ONOO<sup>¯</sup>] balance. To achieve this, metalloporphyrin nanosensors have been effectively employed for real-time, <em>in-situ</em> measurement of NO and ONOO<sup>¯</sup> concentrations (200–300 nm diameter) were applied and precisely positioned 4–5 ± 1 μm from hNPCs membranes, enabling precise investigation of the [NO]/[ONOO<sup>¯</sup>] ratio. The [NO]/[ONOO<sup>¯</sup>] ratio emerged as a critical biomarker for the evaluation of nNOS coupling/uncoupling to the hNPC functioning/dysfunction. In healthy cells, this ratio was around 0.25 ± 0.005, While dysfunctional hNPCs treated to amyloid beta 42 (Aβ<sub>42</sub>)—a hallmark of AD—caused a dramatic 94 % drop, signaling severe cellular dysfunction. Based on these findings, potential pharmacological interventions have been proposed to prevent or reduce AD progression by restoring the [NO]/[ONOO<sup>¯</sup>] balance. Notably, a co-treatment of sepiapterin (SEP), a cofactor precursor for NO synthesis, with VAS 2870 (an NADPH oxidase inhibitor) partially restored the ratio to 0.1, indicating improved nNOS function.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113073"},"PeriodicalIF":3.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084763","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 : 2025-09-15DOI: 10.1016/j.jinorgbio.2025.113077
Imma Carbo-Bague , Parmissa Randhawa , Marianna Tosato , Brooke L. McNeil , Milena Čolović , Lucas London , Cristina Rodríguez-Rodríguez , Maryam Osooly , Luke Wharton , Helen Merkens , Michiel Van De Voorde , Maarten Ooms , Hua Yang , François Bénard , Caterina F. Ramogida
The growing availability of new radiometals with favorable decay properties for cancer diagnosis and therapy highlights the need for chelators that can stably bind a variety of metal ions. 1-Hydroxy-2(1H)-pyridinones (1,2-HOPOs) are effective bidentate ligands with strong affinity for trivalent and tetravalent metals. In this study, we developed a bifunctional octadentate 1,2-HOPO chelator with a methyl tetrazine (Me-Tz) moiety, HOPO-O8-Me-Tz, and evaluated its coordination to [89Zr]Zr4+, [161Tb]Tb3+, and [227Th]Th4+ for theranostic applications. HOPO-O8-Me-Tz was conjugated to HER2/neu targeting antibody Trastuzumab (Tmab), modified with transcyclooctene (TCO), using the inverse electron demand Diels-Alder (IEDDA) click reaction to yield HOPO-O8-Tmab. Radiolabeled conjugates were synthesized under mild conditions (30 min, ambient temperature) and evaluated in vitro and in vivo in SKOV-3 tumour-bearing nude mice. All radiometal complexes demonstrated high stability in serum over 7 days. In vivo, [89Zr]Zr-, [161Tb]Tb- and [227Th]Th-HOPO-O8-Tmab showed high tumour uptake (9.87 ± 3.57, 11.29 ± 4.14 and 19.40 ± 5.40 %ID/g, respectively). Notably, [161Tb]Tb- and [227Th]Th-conjugates exhibited low bone uptake at 96 h post-injection, indicating excellent in vivo stability. The potential redistribution of the alpha-emitting daughter nuclide [223Ra]Ra2+ from [227Th]Th-HOPO-O8-Tmab was assessed, revealing elevated 223Ra in the bone and joint. These findings underscore the promise of HOPO-O8-Me-Tz as a versatile bifunctional chelator for next-generation theranostic radioimmunoconjugates, while also highlighting the importance of managing daughter radionuclide redistribution in alpha therapy.
{"title":"Synthesis and evaluation of HOPO-O8-Methyl-tetrazine as a bifunctional chelator for use in [89Zr]Zr4+, [161Tb]Tb3+ and [227Th]Th4+ radioimmunoconjugates","authors":"Imma Carbo-Bague , Parmissa Randhawa , Marianna Tosato , Brooke L. McNeil , Milena Čolović , Lucas London , Cristina Rodríguez-Rodríguez , Maryam Osooly , Luke Wharton , Helen Merkens , Michiel Van De Voorde , Maarten Ooms , Hua Yang , François Bénard , Caterina F. Ramogida","doi":"10.1016/j.jinorgbio.2025.113077","DOIUrl":"10.1016/j.jinorgbio.2025.113077","url":null,"abstract":"<div><div>The growing availability of new radiometals with favorable decay properties for cancer diagnosis and therapy highlights the need for chelators that can stably bind a variety of metal ions. 1-Hydroxy-2(<em>1</em>H)-pyridinones (1,2-HOPOs) are effective bidentate ligands with strong affinity for trivalent and tetravalent metals. In this study, we developed a bifunctional octadentate 1,2-HOPO chelator with a methyl tetrazine (Me-Tz) moiety, HOPO-O<sub>8</sub>-Me-Tz, and evaluated its coordination to [<sup>89</sup>Zr]Zr<sup>4+</sup>, [<sup>161</sup>Tb]Tb<sup>3+</sup>, and [<sup>227</sup>Th]Th<sup>4+</sup> for theranostic applications. HOPO-O<sub>8</sub>-Me-Tz was conjugated to HER2/<em>neu</em> targeting antibody Trastuzumab (Tmab), modified with transcyclooctene (TCO), using the inverse electron demand Diels-Alder (IEDDA) click reaction to yield HOPO-O<sub>8</sub>-Tmab. Radiolabeled conjugates were synthesized under mild conditions (30 min, ambient temperature) and evaluated <em>in vitro</em> and <em>in vivo</em> in SKOV-3 tumour-bearing nude mice. All radiometal complexes demonstrated high stability in serum over 7 days. <em>In vivo</em>, [<sup>89</sup>Zr]Zr-, [<sup>161</sup>Tb]Tb- and [<sup>227</sup>Th]Th-HOPO-O<sub>8</sub>-Tmab showed high tumour uptake (9.87 ± 3.57, 11.29 ± 4.14 and 19.40 ± 5.40 %ID/g, respectively). Notably, [<sup>161</sup>Tb]Tb- and [<sup>227</sup>Th]Th-conjugates exhibited low bone uptake at 96 h post-injection, indicating excellent <em>in vivo</em> stability. The potential redistribution of the alpha-emitting daughter nuclide [<sup>223</sup>Ra]Ra<sup>2+</sup> from [<sup>227</sup>Th]Th-HOPO-O<sub>8</sub>-Tmab was assessed, revealing elevated <sup>223</sup>Ra in the bone and joint. These findings underscore the promise of HOPO-O<sub>8</sub>-Me-Tz as a versatile bifunctional chelator for next-generation theranostic radioimmunoconjugates, while also highlighting the importance of managing daughter radionuclide redistribution in alpha therapy.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113077"},"PeriodicalIF":3.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090946","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 : 2025-09-15DOI: 10.1016/j.jinorgbio.2025.113076
J.A. Cowan
Cellular mobilization of heme and iron‑sulfur cluster cofactors has been a topic of interest for over a decade. Recognition of glutathione-complexed clusters as viable mediators of intracellular trafficking of [2Fe-2S] cofactors and other metallosubstrates for transmembrane localization has been demonstrated both biochemically and by structural studies, and is supported by genetic analysis. Sequence and structural correlations of both eukaryotic and prokaryotic ATP-binding cassette (ABC) membrane transporter families (ABCB7 and ABCB6) reveals connections that address possible roles for ABCB6 in Fe-S cluster cellular mobilization and further clarify its role in heme transport. This review expands on these themes by correlating structural and sequence relationships between Fe-S cluster and heme transporters, and broader roles in mediating drug resistance and elimination of toxic metals.
{"title":"Structural and sequence basis for substrate selection in the cellular trafficking of Fe-S clusters, hemes and glutathione-complexed metals through membrane transporters","authors":"J.A. Cowan","doi":"10.1016/j.jinorgbio.2025.113076","DOIUrl":"10.1016/j.jinorgbio.2025.113076","url":null,"abstract":"<div><div>Cellular mobilization of heme and iron‑sulfur cluster cofactors has been a topic of interest for over a decade. Recognition of glutathione-complexed clusters as viable mediators of intracellular trafficking of [2Fe-2S] cofactors and other metallosubstrates for transmembrane localization has been demonstrated both biochemically and by structural studies, and is supported by genetic analysis. Sequence and structural correlations of both eukaryotic and prokaryotic ATP-binding cassette (ABC) membrane transporter families (ABCB7 and ABCB6) reveals connections that address possible roles for ABCB6 in Fe-S cluster cellular mobilization and further clarify its role in heme transport. This review expands on these themes by correlating structural and sequence relationships between Fe-S cluster and heme transporters, and broader roles in mediating drug resistance and elimination of toxic metals.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113076"},"PeriodicalIF":3.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249161","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 : 2025-09-13DOI: 10.1016/j.jinorgbio.2025.113071
Florian J. Fekete, Emily E. Weinert
The heme cofactor is found across all domains of life, serving a variety of purposes, such as gas transport, catalysis of reactions, and gas sensing. Heme-based gas sensors bind NO, CO, and O2, modulating cellular responses to these ligands. The widespread nature of heme proteins and the importance of oxygen to most life forms make them an intriguing system to investigate the role of heme proteins and bacterial oxygen response. Bacteria use various classes of heme sensors to detect oxygen signals, including heme-containing Per-Arnt-Sim (hPAS), and sensor globin domain-containing proteins. Globin coupled sensor (GCS) proteins have emerged as another widespread heme-based O2 sensing protein family, providing insights into stabilization of O2 binding and ligand-selective signaling. GCS proteins also are useful as models for intracellular cyclic-di-guanosine monophosphate (c-di-GMP) signaling, as the most extensively studied group of GCS proteins contain diguanylate cyclase (DGC) output domains, which synthesize c-di-GMP upon ligand binding. These proteins, such as Escherichia coli EcDosC (Direct Oxygen Sensor Cyclase), Pectobacterium carotovorum PccDgcO, and Bordetella pertussis BpeGReg, have been investigated regarding their heme characteristics, biochemistry, and roles in modulating bacterial response to O2. In addition, the interaction between the E. coli hPAS protein DosP and the GCS DosC highlight the complex systems used to control downstream bacterial response to environmental oxygen.
{"title":"Roles of biological heme-based sensors of O2 in controlling bacterial behavior","authors":"Florian J. Fekete, Emily E. Weinert","doi":"10.1016/j.jinorgbio.2025.113071","DOIUrl":"10.1016/j.jinorgbio.2025.113071","url":null,"abstract":"<div><div>The heme cofactor is found across all domains of life, serving a variety of purposes, such as gas transport, catalysis of reactions, and gas sensing. Heme-based gas sensors bind NO, CO, and O<sub>2</sub>, modulating cellular responses to these ligands. The widespread nature of heme proteins and the importance of oxygen to most life forms make them an intriguing system to investigate the role of heme proteins and bacterial oxygen response. Bacteria use various classes of heme sensors to detect oxygen signals, including heme-containing Per-Arnt-Sim (hPAS), and sensor globin domain-containing proteins. Globin coupled sensor (GCS) proteins have emerged as another widespread heme-based O<sub>2</sub> sensing protein family, providing insights into stabilization of O<sub>2</sub> binding and ligand-selective signaling. GCS proteins also are useful as models for intracellular cyclic-di-guanosine monophosphate (<em>c</em>-di-GMP) signaling, as the most extensively studied group of GCS proteins contain diguanylate cyclase (DGC) output domains, which synthesize <em>c</em>-di-GMP upon ligand binding. These proteins, such as <em>Escherichia coli Ec</em>DosC (Direct Oxygen Sensor Cyclase), <em>Pectobacterium carotovorum Pcc</em>DgcO, and <em>Bordetella pertussis Bpe</em>GReg, have been investigated regarding their heme characteristics, biochemistry, and roles in modulating bacterial response to O<sub>2</sub>. In addition, the interaction between the <em>E. coli</em> hPAS protein DosP and the GCS DosC highlight the complex systems used to control downstream bacterial response to environmental oxygen.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"275 ","pages":"Article 113071"},"PeriodicalIF":3.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090972","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 : 2025-09-12DOI: 10.1016/j.jinorgbio.2025.113069
{"title":"Larry Que: Reflections from a life in science","authors":"","doi":"10.1016/j.jinorgbio.2025.113069","DOIUrl":"10.1016/j.jinorgbio.2025.113069","url":null,"abstract":"","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113069"},"PeriodicalIF":3.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204958","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 : 2025-09-12DOI: 10.1016/j.jinorgbio.2025.113070
Meixuan Zhang , Qin Zhang , Xuemin Mu , Xiaolin Wang , Shuhui Zhang , Wenyi Zhao , Xiaoming Song , Lulu Pan , Yanyan Li
The escalating threat of bacterial infections underscores the pressing need for innovative antibacterial solutions. In this study, BA-BBR@MPN nanoparticles (BA-BBR@MPN NPs) were synthesized through the self-assembly of berberine (BBR) and baicalin (BA), followed by modification with a metal-phenolic network (MPN) derived from caffeic acid and Fe3+. In the slightly acidic environment of the infected site, the MPN decomposes to release iron ions, BBR, and BA. The iron ions catalyze the generation of hydroxyl radicals (·OH) from hydrogen peroxide (H2O2), enabling chemodynamic therapy (CDT) while simultaneously depleting glutathione levels. When combined with 808 nm laser-induced photothermal therapy (PTT), the system demonstrates synergistic antibacterial effects. Both in vitro and in vivo studies confirmed the platform's broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria, along with excellent biocompatibility and significant wound-healing promotion. This multifunctional nanoplatform represents a promising strategy for combating bacterial infections while simultaneously promoting tissue repair.
{"title":"Caffeic acid-Fe3+ nanohybrids loaded with berberine/baicalin for NIR-activated antibacterial therapy via ROS generation and photothermal effects","authors":"Meixuan Zhang , Qin Zhang , Xuemin Mu , Xiaolin Wang , Shuhui Zhang , Wenyi Zhao , Xiaoming Song , Lulu Pan , Yanyan Li","doi":"10.1016/j.jinorgbio.2025.113070","DOIUrl":"10.1016/j.jinorgbio.2025.113070","url":null,"abstract":"<div><div>The escalating threat of bacterial infections underscores the pressing need for innovative antibacterial solutions. In this study, BA-BBR@MPN nanoparticles (BA-BBR@MPN NPs) were synthesized through the self-assembly of berberine (BBR) and baicalin (BA), followed by modification with a metal-phenolic network (MPN) derived from caffeic acid and Fe<sup>3+</sup>. In the slightly acidic environment of the infected site, the MPN decomposes to release iron ions, BBR, and BA. The iron ions catalyze the generation of hydroxyl radicals (·OH) from hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), enabling chemodynamic therapy (CDT) while simultaneously depleting glutathione levels. When combined with 808 nm laser-induced photothermal therapy (PTT), the system demonstrates synergistic antibacterial effects. Both in vitro and in vivo studies confirmed the platform's broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria, along with excellent biocompatibility and significant wound-healing promotion. This multifunctional nanoplatform represents a promising strategy for combating bacterial infections while simultaneously promoting tissue repair.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"274 ","pages":"Article 113070"},"PeriodicalIF":3.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145106368","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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