Pub Date : 2026-01-17DOI: 10.1016/j.jinorgbio.2026.113236
Xing-Yi Zhu , Zhen-Lang Xie , Si-Yuan Wang , Wan-Ting Jin , Zhao-Hui Zhou
Enantiomerically pure iron(II/III) lactates Λ-FeII(S-Hlact)2(H2O)2 (1), Na[Λ-FeIII(S-Hlact)2(S-lact)]·3.5H2O (2a) and Na[Δ-FeIII(R-Hlact)2(R-lact)]·3.5H2O (2b), along with iron(II/III) citrates (H2pz)2[FeIII2(cit)2(H2O)2]·2H2O (3) and [FeII(Hpz)4]n[FeIII2(cit)2(Hpz)2]n·2n(Hpz)·0.25nH2O (4) (H2lact = lactic acid, H4cit = citric acid, Hpz = pyrazole) have been obtained. In 1 and 2, lactates chelate with iron bidentately through α-hydroxy/α-alkoxy and α-carboxy groups, respectively, forming stable five-membered chelated rings. Strong intermolecular hydrogen bonds have been found between α-hydroxy and α-alkoxy groups, with strong electron delocalization. For 3, citrate chelates one of the iron centers in a tridentate mode via its α-alkoxy, α-carboxy, and β-carboxy groups, leaving protonated pyrazole free. Further substitution of the coordinated water molecule in 3 results in the formation of mixed-valent pyrazole iron(II/III) citrate 4. The iron lactates and citrates show resemblance to the local environment of the active site of homocitrate and imidazole-coordinated FeFe-cofactor in Fe-only nitrogenase. The biological relevance has been discussed in details.
{"title":"Iron(II/III) α-hydroxycarboxylates toward the local coordination environments of FeFe-cofactor in Fe‑nitrogenase","authors":"Xing-Yi Zhu , Zhen-Lang Xie , Si-Yuan Wang , Wan-Ting Jin , Zhao-Hui Zhou","doi":"10.1016/j.jinorgbio.2026.113236","DOIUrl":"10.1016/j.jinorgbio.2026.113236","url":null,"abstract":"<div><div>Enantiomerically pure iron(II/III) lactates Λ-Fe<sup>II</sup>(<em>S</em>-Hlact)<sub>2</sub>(H<sub>2</sub>O)<sub>2</sub> (<strong>1</strong>), Na[Λ-Fe<sup>III</sup>(<em>S</em>-Hlact)<sub>2</sub>(<em>S</em>-lact)]·3.5H<sub>2</sub>O (<strong>2a</strong>) and Na[Δ-Fe<sup>III</sup>(<em>R</em>-Hlact)<sub>2</sub>(<em>R</em>-lact)]·3.5H<sub>2</sub>O (<strong>2b</strong>), along with iron(II/III) citrates (H<sub>2</sub>pz)<sub>2</sub>[Fe<sup>III</sup><sub>2</sub>(cit)<sub>2</sub>(H<sub>2</sub>O)<sub>2</sub>]·2H<sub>2</sub>O (<strong>3</strong>) and [Fe<sup>II</sup>(Hpz)<sub>4</sub>]<sub>n</sub>[Fe<sup>III</sup><sub>2</sub>(cit)<sub>2</sub>(Hpz)<sub>2</sub>]<sub>n</sub>·2n(Hpz)·0.25nH<sub>2</sub>O (<strong>4</strong>) (H<sub>2</sub>lact = lactic acid, H<sub>4</sub>cit = citric acid, Hpz = pyrazole) have been obtained. In <strong>1</strong> and <strong>2</strong>, lactates chelate with iron bidentately through α-hydroxy/α-alkoxy and α-carboxy groups, respectively, forming stable five-membered chelated rings. Strong intermolecular hydrogen bonds have been found between α-hydroxy and α-alkoxy groups, with strong electron delocalization. For <strong>3</strong>, citrate chelates one of the iron centers in a tridentate mode <em>via</em> its α-alkoxy, α-carboxy, and β-carboxy groups, leaving protonated pyrazole free. Further substitution of the coordinated water molecule in <strong>3</strong> results in the formation of mixed-valent pyrazole iron(II/III) citrate <strong>4</strong>. The iron lactates and citrates show resemblance to the local environment of the active site of homocitrate and imidazole-coordinated FeFe-cofactor in Fe-only nitrogenase. The biological relevance has been discussed in details.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113236"},"PeriodicalIF":3.2,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1016/j.jinorgbio.2026.113237
Alissa Lance-Byrne , Juliet C. Gee , Timothy C. Johnstone
Sodium stibogluconate is an effective but toxic Sb-containing antileishmanial drug. Despite having been in clinical use for over half a century, the chemical structure of this small-molecule drug remains unknown. Historically, the drug has been thought to comprise an intractable mixture of interconverting species. We report here nuclear magnetic resonance (NMR) spectroscopic experiments that provide the first evidence that the reaction between gluconate and [Sb(OH)6]− produces primarily one molecular species. Multidimensional experiments allow the NMR resonances of this species to be fully assigned. Further experiments on authentic samples and clinical preparations of sodium stibogluconate confirm that the primary product of the reaction of gluconate and [Sb(OH)6]− is the predominant antimony-containing component of the drug. The thermodynamic stability of this predominant species was assessed using a combination of 1H and 121Sb NMR spectroscopic measurements, which afforded a value of K = 1006 M−1 for its formation from gluconate and [Sb(OH)6]−.
{"title":"NMR spectroscopic evidence that the antileishmanial drug sodium stibogluconate comprises one predominant molecular species","authors":"Alissa Lance-Byrne , Juliet C. Gee , Timothy C. Johnstone","doi":"10.1016/j.jinorgbio.2026.113237","DOIUrl":"10.1016/j.jinorgbio.2026.113237","url":null,"abstract":"<div><div>Sodium stibogluconate is an effective but toxic Sb-containing antileishmanial drug. Despite having been in clinical use for over half a century, the chemical structure of this small-molecule drug remains unknown. Historically, the drug has been thought to comprise an intractable mixture of interconverting species. We report here nuclear magnetic resonance (NMR) spectroscopic experiments that provide the first evidence that the reaction between gluconate and [Sb(OH)<sub>6</sub>]<sup>−</sup> produces primarily one molecular species. Multidimensional experiments allow the NMR resonances of this species to be fully assigned. Further experiments on authentic samples and clinical preparations of sodium stibogluconate confirm that the primary product of the reaction of gluconate and [Sb(OH)<sub>6</sub>]<sup>−</sup> is the predominant antimony-containing component of the drug. The thermodynamic stability of this predominant species was assessed using a combination of <sup>1</sup>H and <sup>121</sup>Sb NMR spectroscopic measurements, which afforded a value of <em>K</em> = 1006 M<sup>−1</sup> for its formation from gluconate and [Sb(OH)<sub>6</sub>]<sup>−</sup>.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113237"},"PeriodicalIF":3.2,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1016/j.jinorgbio.2026.113235
M. Kubeil , H. Stephan
Carbon monoxide-releasing molecules (CORMs) have drawn attention since the beginning of the century. Since then, many publications have been devoted to optimizing the physicochemical properties of CORMs, with a focus on the release kinetics of CO as a function of external stimuli such as light, enzyme, and redox triggering, as well as ligand exchange and pH changes. This was followed by studies on the use of CORMs and later carbon monoxide-releasing nanomaterials (CORNMs) as pharmaceutical active compounds/materials in biological systems. In this context, there is an ongoing debate as to whether the pharmacological efficacy can be clearly attributed to CO alone or whether CO-free metal fragments or both mechanisms contribute to biological efficacy. This review focuses in particular on CORMs and CORNMs that exhibit cell toxicity and on corresponding characterization methods that allow biological efficacy to be assigned. The methods to be used to obtain reliable information on biodistribution and pharmacokinetic properties, as well as the characterization of the kinetics of controlled CO release in living organisms, are outlined.
{"title":"Cytotoxicity of metal-containing carbon monoxide-releasing molecules: A current assessment","authors":"M. Kubeil , H. Stephan","doi":"10.1016/j.jinorgbio.2026.113235","DOIUrl":"10.1016/j.jinorgbio.2026.113235","url":null,"abstract":"<div><div>Carbon monoxide-releasing molecules (CORMs) have drawn attention since the beginning of the century. Since then, many publications have been devoted to optimizing the physicochemical properties of CORMs, with a focus on the release kinetics of CO as a function of external stimuli such as light, enzyme, and redox triggering, as well as ligand exchange and pH changes. This was followed by studies on the use of CORMs and later carbon monoxide-releasing nanomaterials (CORNMs) as pharmaceutical active compounds/materials in biological systems. In this context, there is an ongoing debate as to whether the pharmacological efficacy can be clearly attributed to CO alone or whether CO-free metal fragments or both mechanisms contribute to biological efficacy. This review focuses in particular on CORMs and CORNMs that exhibit cell toxicity and on corresponding characterization methods that allow biological efficacy to be assigned. The methods to be used to obtain reliable information on biodistribution and pharmacokinetic properties, as well as the characterization of the kinetics of controlled CO release in living organisms, are outlined.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113235"},"PeriodicalIF":3.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008281","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 : 2026-01-13DOI: 10.1016/j.jinorgbio.2026.113228
Yun-hou Huang , Yuan Liu , Yue Huang , Wei-ying Meng , Hong-zu Wei , Chang-chun Wen , Li-min Liu , Yan-cheng Liu
Norcantharidin (NCTD) is a structurally modified derivative of cantharidin, which is an active component derived from traditional Chinese medicine (TCM) and exhibiting specific anticancer activity. In this work, four pH-sensitive complexes of NCTD, with cationic 2-aminopyridine (AP) as the counter ion, were successfully synthesized and structurally characterized. The crystal structures resolved by single crystal X-ray diffraction analysis demonstrated that they all formed in complexes with ionic type, 2AP[M(NCTD)2], (M = Cu, Co, Ni and Mn), composed of the negative divalent six-coordinated species, [M(NCTD)2]2−, and two counter cations (AP). Our findings demonstrated that under slightly acidic conditions (pH = 6.6), the decomposition of 2AP[M(NCTD)2] (M = Cu, Co, Ni, and Mn) led to the release of NCTD and metal ions, which subsequently triggered a Fenton-like reaction co-catalyzed by GSH. They exhibited stronger in vitro anticancer properties than NCTD against a series of typical cancer cell lines tested, with the IC50 values in the range of 12.41–33.43 μM, in which 2AP[Cu(NCTD)2], showed the best efficacy. In the most sensitive SK-OV-3 cells, 2AP[Cu(NCTD)2], induced mitochondrial dysfunction by triggering the excessive accumulation of ROS within mitochondria, thereby activating the apoptotic pathway. Meanwhile, 2AP[Cu(NCTD)2], could obviously arrest the cell cycle at Sub-G1 phase in SK-OV-3 cells.
{"title":"Discovery, crystal structure, anticancer property of the first-row transition metal complexes of norcantharidin (NCTD) as potential inducer of mitochondrial damage","authors":"Yun-hou Huang , Yuan Liu , Yue Huang , Wei-ying Meng , Hong-zu Wei , Chang-chun Wen , Li-min Liu , Yan-cheng Liu","doi":"10.1016/j.jinorgbio.2026.113228","DOIUrl":"10.1016/j.jinorgbio.2026.113228","url":null,"abstract":"<div><div>Norcantharidin (<strong>NCTD</strong>) is a structurally modified derivative of cantharidin, which is an active component derived from traditional Chinese medicine (TCM) and exhibiting specific anticancer activity. In this work, four pH-sensitive complexes of <strong>NCTD</strong>, with cationic 2-aminopyridine (<strong>AP</strong>) as the counter ion, were successfully synthesized and structurally characterized. The crystal structures resolved by single crystal X-ray diffraction analysis demonstrated that they all formed in complexes with ionic type, <strong>2AP[M(NCTD)</strong><sub><strong>2</strong></sub><strong>]</strong>, (<strong>M</strong> = <strong>Cu</strong>, <strong>Co</strong>, <strong>Ni</strong> and <strong>Mn</strong>), composed of the negative divalent six-coordinated species, <strong>[M(NCTD)</strong><sub><strong>2</strong></sub><strong>]</strong><sup><strong>2−</strong></sup>, and two counter cations (<strong>AP</strong>). Our findings demonstrated that under slightly acidic conditions (pH = 6.6), the decomposition of <strong>2AP[M(NCTD)</strong><sub><strong>2</strong></sub><strong>]</strong> (M = Cu, Co, Ni, and Mn) led to the release of <strong>NCTD</strong> and metal ions, which subsequently triggered a Fenton-like reaction co-catalyzed by GSH. They exhibited stronger <em>in vitro</em> anticancer properties than <strong>NCTD</strong> against a series of typical cancer cell lines tested, with the IC<sub>50</sub> values in the range of 12.41–33.43 μM, in which <strong>2AP[Cu(NCTD)</strong><sub><strong>2</strong></sub><strong>]</strong>, showed the best efficacy. In the most sensitive SK-OV-3 cells, <strong>2AP[Cu(NCTD)</strong><sub><strong>2</strong></sub><strong>]</strong>, induced mitochondrial dysfunction by triggering the excessive accumulation of ROS within mitochondria, thereby activating the apoptotic pathway. Meanwhile, <strong>2AP[Cu(NCTD)</strong><sub><strong>2</strong></sub><strong>]</strong>, could obviously arrest the cell cycle at Sub-G<sub>1</sub> phase in SK-OV-3 cells.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113228"},"PeriodicalIF":3.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002798","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 : 2026-01-12DOI: 10.1016/j.jinorgbio.2026.113229
Trinidad Arcos-López , Hyeongtaek Lim , Britt Hedman , Keith O. Hodgson , Alberto Vela , Claudio O. Fernández-Outón , Edward I. Solomon , Liliana Quintanar
Amyloid aggregation of alpha-synuclein (AS) protein is associated with Parkinson's disease. Physiologically, AS plays a crucial role in the uptake, storage, and recycling of neurotransmitter vesicles. AS has three independent binding sites for Cu(II) and Cu(I) ions. N-terminal acetylation of AS impacts the highest-affinity site of Cu, encompassing the first five residues; it prevents Cu(II) coordination, enhances Cu(I) binding affinity, raises its redox potential, and extends the α-helix to the first ten residues. In this study, X-ray absorption spectroscopy and electronic structure calculations are employed to provide a detailed molecular description of the highest affinity Cu(I) binding site in AS, both in the acetylated AS (AcAS) and non-acetylated forms of the protein. The roles of methionine residues Met1 and Met5 in Cu(I) binding are also evaluated using peptide fragment models. Our findings indicate that in both cases, the coordination sphere is tetracoordinated, with the two sulfur atoms from Met1 and Met5 serving as the primary anchors for Cu(I) coordination. At the same time, Met1 plays a crucial role in stabilizing Cu(I). While both complexes include the carboxylate oxygen of Asp2, a key difference lies in the fourth ligand: the Cu(I)-AS complex utilizes the N-terminal group, whereas the Cu(I)-AcAS complex uses a carbonyl oxygen from the N-terminal acetyl group. These results provide deeper insights into how acetylation impacts the chemical properties of the high-affinity copper binding site in AS and contribute to a better understanding of the role of Cu(I) binding in the physiological function of AS.
{"title":"Impact of N-terminal acetylation on Cu(I) coordination by alpha synuclein protein","authors":"Trinidad Arcos-López , Hyeongtaek Lim , Britt Hedman , Keith O. Hodgson , Alberto Vela , Claudio O. Fernández-Outón , Edward I. Solomon , Liliana Quintanar","doi":"10.1016/j.jinorgbio.2026.113229","DOIUrl":"10.1016/j.jinorgbio.2026.113229","url":null,"abstract":"<div><div>Amyloid aggregation of alpha-synuclein (AS) protein is associated with Parkinson's disease. Physiologically, AS plays a crucial role in the uptake, storage, and recycling of neurotransmitter vesicles. AS has three independent binding sites for Cu(II) and Cu(I) ions. N-terminal acetylation of AS impacts the highest-affinity site of Cu, encompassing the first five residues; it prevents Cu(II) coordination, enhances Cu(I) binding affinity, raises its redox potential, and extends the α-helix to the first ten residues. In this study, X-ray absorption spectroscopy and electronic structure calculations are employed to provide a detailed molecular description of the highest affinity Cu(I) binding site in AS, both in the acetylated AS (AcAS) and non-acetylated forms of the protein. The roles of methionine residues Met1 and Met5 in Cu(I) binding are also evaluated using peptide fragment models. Our findings indicate that in both cases, the coordination sphere is tetracoordinated, with the two sulfur atoms from Met1 and Met5 serving as the primary anchors for Cu(I) coordination. At the same time, Met1 plays a crucial role in stabilizing Cu(I). While both complexes include the carboxylate oxygen of Asp2, a key difference lies in the fourth ligand: the Cu(I)-AS complex utilizes the N-terminal group, whereas the Cu(I)-AcAS complex uses a carbonyl oxygen from the N-terminal acetyl group. These results provide deeper insights into how acetylation impacts the chemical properties of the high-affinity copper binding site in AS and contribute to a better understanding of the role of Cu(I) binding in the physiological function of AS.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113229"},"PeriodicalIF":3.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058371","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 : 2026-01-12DOI: 10.1016/j.jinorgbio.2026.113230
Matthias Huber, Corinna R. Hess
The modified macrocyclic Mabiq ligand, MeOMbq, contains two methoxy groups at the outer biquinazoline unit that allow for coordination of a second metal ion in the absence of auxiliary ligands. A series of bimetallic MFeMeOMbq complexes was synthesized, containing Na, Mg, Fe or Zn adjacent to a centrally bound ferrous ion. The redox properties correlate with the Lewis acidity of the supporting metal. Both Fe and Zn in the outer site boost the photocatalytic CO2 reduction activity of the central ferrous site. The bimetallic ZnFeMeOMbq achieves up to 140 TONs (1 h) for selective CO2 to CO conversion in a self-sensitized process.
{"title":"Lewis acid-promoted self-sensitized photocatalytic CO2 reduction by a bimetallic Fe complex","authors":"Matthias Huber, Corinna R. Hess","doi":"10.1016/j.jinorgbio.2026.113230","DOIUrl":"10.1016/j.jinorgbio.2026.113230","url":null,"abstract":"<div><div>The modified macrocyclic Mabiq ligand, <sup><strong>MeO</strong></sup><strong>Mbq</strong>, contains two methoxy groups at the outer biquinazoline unit that allow for coordination of a second metal ion in the absence of auxiliary ligands. A series of bimetallic <strong>MFe</strong><sup><strong>MeO</strong></sup><strong>Mbq</strong> complexes was synthesized, containing Na, Mg, Fe or Zn adjacent to a centrally bound ferrous ion. The redox properties correlate with the Lewis acidity of the supporting metal. Both Fe and Zn in the outer site boost the photocatalytic CO<sub>2</sub> reduction activity of the central ferrous site. The bimetallic <strong>ZnFe</strong><sup><strong>MeO</strong></sup><strong>Mbq</strong> achieves up to 140 TONs (1 h) for selective CO<sub>2</sub> to CO conversion in a self-sensitized process.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113230"},"PeriodicalIF":3.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023367","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 : 2026-01-09DOI: 10.1016/j.jinorgbio.2026.113225
Marco A. Tiburcio , Bárbara Patrícia N. Silva , Maria Laura da C. Garcia , Lorena M.B. Pereira , Marina M. Grigoli , Márcia R. Cominetti , Rose M. Carlos
Intranasal insulin therapy for Alzheimer's disease (AD) has received increasing attention due to its potential to modulate amyloid-β (Aβ) aggregation, a hallmark of AD pathology. Molecular dynamics simulations suggest that insulin binds across U-shaped Aβ1–42oligomers, disrupting β-strand alignment via its A-chain. In contrast, the Ru(II) complex cis-[Ru(phen)2(3,4Apy)₂]2+(Ru3,4Apy; phen = 1,10-phenanthroline; 3,4Apy = 3,4-aminopyridine) primarily interacts with fibril surfaces. Although both target the central hydrophobic core motif, they bind to distinct regions of Aβ1–42. Their co-aggregation with Aβ1–42 may thus influence aggregation and cytotoxicity differently, providing insight into the molecular mechanisms underlying insulin's mitigation of Aβ-induced cytotoxicity. We monitored Aβ1–42 aggregation using Tyr10 intrinsic fluorescence, circular dichroism, atomic force microscopy, and SH-SY5Y cell viability assays in the presence of insulin, Ru3,4Apy, or both. Ru3,4Apy reduced β-sheet formation but did not prevent Aβ1–42-induced cytotoxicity. In contrast, insulin limited conformational flexibility, prevented Tyr10 burial, suppressed β-sheet formation, and promoted amorphous, non-toxic aggregates. Notable, in the Aβ1–42/Ru3,4Apy/Insulin mixture, aggregation followed a non-toxic pathway bypassing the buried-core β-sheet typical of mature fibrils. These findings emphasize the specificity of Aβ1–42/Insulin interactions and suggest targeting defined binding sites as a promising AD therapeutic strategy.
{"title":"Insulin modulates Aβ1–42 aggregation toward non-toxic forms: A comparative study with cis-[Ru(phen)2(3,4Apy)2]2+","authors":"Marco A. Tiburcio , Bárbara Patrícia N. Silva , Maria Laura da C. Garcia , Lorena M.B. Pereira , Marina M. Grigoli , Márcia R. Cominetti , Rose M. Carlos","doi":"10.1016/j.jinorgbio.2026.113225","DOIUrl":"10.1016/j.jinorgbio.2026.113225","url":null,"abstract":"<div><div>Intranasal insulin therapy for Alzheimer's disease (AD) has received increasing attention due to its potential to modulate amyloid-β (Aβ) aggregation, a hallmark of AD pathology. <strong>Molecular dynamics simulations suggest that insulin binds across U-shaped Aβ</strong><sub><strong>1</strong></sub><sub><strong>–</strong></sub><sub><strong>42</strong></sub> <strong>oligomers, disrupting β-strand alignment via its A-chain. In contrast, the Ru(II) complex <em>cis</em>-[Ru(phen)</strong><sub><strong>2</strong></sub><strong>(3,4Apy)₂]</strong><sup><strong>2+</strong></sup> <strong>(Ru3,4Apy; phen = 1,10-phenanthroline; 3,4Apy = 3,4-aminopyridine) primarily interacts with fibril surfaces. Although both target the central hydrophobic core motif, they bind to distinct regions of Aβ</strong><sub><strong>1</strong></sub><sub><strong>–</strong></sub><sub><strong>42</strong></sub><strong>.</strong> Their co-aggregation with Aβ<sub>1</sub><sub>–</sub><sub>42</sub> may thus influence aggregation and cytotoxicity differently, providing insight into <strong>the molecular mechanisms underlying insulin's mitigation of Aβ-induced cytotoxicity</strong>. We monitored Aβ<sub>1</sub><sub>–</sub><sub>42</sub> aggregation using Tyr10 intrinsic fluorescence, circular dichroism, atomic force microscopy, and SH-SY5Y cell viability assays in the presence of insulin, Ru3,4Apy, or both. Ru3,4Apy reduced β-sheet formation but did not prevent <strong>Aβ</strong><sub><strong>1</strong></sub><sub><strong>–</strong></sub><sub><strong>42</strong></sub><strong>-induced cytotoxicity</strong>. In contrast, insulin limited conformational flexibility, prevented Tyr10 burial, suppressed β-sheet formation, and promoted amorphous, non-toxic aggregates. Notable, in the Aβ<sub>1</sub><sub>–</sub><sub>42</sub>/Ru3,4Apy/Insulin mixture, aggregation followed a non-toxic pathway bypassing the buried-core β-sheet typical of mature fibrils. These findings emphasize the specificity of Aβ<sub>1</sub><sub>–</sub><sub>42</sub>/Insulin interactions and suggest targeting defined binding sites as a promising AD therapeutic strategy.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113225"},"PeriodicalIF":3.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951085","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 : 2026-01-09DOI: 10.1016/j.jinorgbio.2026.113226
Luwen Zhang, Jiarui Qiao, Junhe Ou, Yan Wang, Tingyan Jiang, Xianhao Wei, Maolin Pang
As a promising noninvasive approach, photodynamic therapy (PDT) has received considerable attention attributed to its preciseness and low toxicity. However, its therapeutic efficacy is largely dependent on the ability of photosensitizers to generate reactive oxygen species (ROS). In this study, a systematic comparison of hydrogen-bonded organic frameworks (HOFs) constructed from different porphyrin units demonstrated that TCPP-Cu-HOF exhibited the narrowest bandgap and the highest ROS generation efficiency under 650 nm laser irradiation, leading to outstanding PDT performance at the cellular level. Based on these results, TCPP-Cu-HOF was further selected for in vivo evaluation, where effective antitumor efficacy was achieved. This work provides a facile synthesis method for HOF nanoparticles and further expands their potential applications in biomedical fields.
光动力疗法（PDT）作为一种很有前途的无创治疗方法，因其准确性和低毒性而受到广泛关注。然而，其治疗效果很大程度上取决于光敏剂产生活性氧（ROS）的能力。在本研究中，系统比较了由不同卟啉单元构建的氢键有机框架（hof），发现在650 nm激光照射下，tpcp - cu - hof具有最窄的带隙和最高的ROS生成效率，从而在细胞水平上具有出色的PDT性能。在此基础上，进一步选择TCPP-Cu-HOF进行体内评价，获得了有效的抗肿瘤效果。本研究为HOF纳米颗粒的合成提供了一种简便的方法，并进一步拓展了其在生物医学领域的潜在应用。
{"title":"Preparation of diverse porphyrins-based hydrogen-bonded organic frameworks for photodynamic cancer therapy","authors":"Luwen Zhang, Jiarui Qiao, Junhe Ou, Yan Wang, Tingyan Jiang, Xianhao Wei, Maolin Pang","doi":"10.1016/j.jinorgbio.2026.113226","DOIUrl":"10.1016/j.jinorgbio.2026.113226","url":null,"abstract":"<div><div>As a promising noninvasive approach, photodynamic therapy (PDT) has received considerable attention attributed to its preciseness and low toxicity. However, its therapeutic efficacy is largely dependent on the ability of photosensitizers to generate reactive oxygen species (ROS). In this study, a systematic comparison of hydrogen-bonded organic frameworks (HOFs) constructed from different porphyrin units demonstrated that TCPP-Cu-HOF exhibited the narrowest bandgap and the highest ROS generation efficiency under 650 nm laser irradiation, leading to outstanding PDT performance at the cellular level. Based on these results, TCPP-Cu-HOF was further selected for <em>in vivo</em> evaluation, where effective antitumor efficacy was achieved. This work provides a facile synthesis method for HOF nanoparticles and further expands their potential applications in biomedical fields.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113226"},"PeriodicalIF":3.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951051","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 : 2026-01-07DOI: 10.1016/j.jinorgbio.2025.113211
Ilia G. Denisov , Yilin Liu , Piotr J. Mak , Stephen G. Sligar
The human cytochrome P450 CYP17A1 plays a critical role in the production of steroid hormones, converting pregnenolone to dehydroepiandrosterone and progesterone to androstenedione. Sequential reactions catalyzed by CYP17A1 are hydroxylation at C17 position, followed by C17 – C20 carbon‑carbon bond scission. The mechanism of the lyase reaction is still debated, with two proposed reaction pathways favoring either a peroxo- (Compond 0) or iron-oxo (Compound 1) driven catalysis. In this review we summarize the results obtained through collaboration between the Sligar laboratory at University of Illinois and the Kincaid laboratory at Marquette University over the last 15 years. We used a combination of spectroscopic and functional studies of human CYP17A1 incorporated in lipid Nanodiscs, mimicking the native membrane environment, to dissect the elementary steps of P450 reaction cycle and characterize the iron‑oxygen intermediates in the presence of substrates for both reactions catalyzed by CYP17A1. In addition, we used the mutations E305G and T306A to probe the effect of perturbing the proton delivery required for the formation of Compound 1, but not for Compound 0, and the mutation N202S involved in substrate positioning at the active site. Resonance Raman spectra, in combination with cryo-radiolytic reduction of the oxy-complex of CYP17A1, provided a detailed picture of hydrogen bonding and protonation of peroxo- and hydroperoxo- intermediates and identified a new transient hemiketal complex on the peroxo-driven pathway of lyase reaction. These results consistently demonstrated the predominant role of the peroxo-driven catalysis for the lyase reaction in CYP17A1 incorporated in lipid Nanodiscs.
{"title":"Mechanistic and spectroscopic characterization of human CYP17A1 in Nanodiscs","authors":"Ilia G. Denisov , Yilin Liu , Piotr J. Mak , Stephen G. Sligar","doi":"10.1016/j.jinorgbio.2025.113211","DOIUrl":"10.1016/j.jinorgbio.2025.113211","url":null,"abstract":"<div><div>The human cytochrome P450 CYP17A1 plays a critical role in the production of steroid hormones, converting pregnenolone to dehydroepiandrosterone and progesterone to androstenedione. Sequential reactions catalyzed by CYP17A1 are hydroxylation at C17 position, followed by C17 – C20 carbon‑carbon bond scission. The mechanism of the lyase reaction is still debated, with two proposed reaction pathways favoring either a peroxo- (Compond 0) or iron-oxo (Compound 1) driven catalysis. In this review we summarize the results obtained through collaboration between the Sligar laboratory at University of Illinois and the Kincaid laboratory at Marquette University over the last 15 years. We used a combination of spectroscopic and functional studies of human CYP17A1 incorporated in lipid Nanodiscs, mimicking the native membrane environment, to dissect the elementary steps of P450 reaction cycle and characterize the iron‑oxygen intermediates in the presence of substrates for both reactions catalyzed by CYP17A1. In addition, we used the mutations E305G and T306A to probe the effect of perturbing the proton delivery required for the formation of Compound 1, but not for Compound 0, and the mutation N202S involved in substrate positioning at the active site. Resonance Raman spectra, in combination with cryo-radiolytic reduction of the oxy-complex of CYP17A1, provided a detailed picture of hydrogen bonding and protonation of peroxo- and hydroperoxo- intermediates and identified a new transient hemiketal complex on the peroxo-driven pathway of lyase reaction. These results consistently demonstrated the predominant role of the peroxo-driven catalysis for the lyase reaction in CYP17A1 incorporated in lipid Nanodiscs.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113211"},"PeriodicalIF":3.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921999","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 : 2026-01-07DOI: 10.1016/j.jinorgbio.2026.113217
Anushka Verma , Arabinda Muley , Nafeesa Shahnaz , Sharan Shanmuga Vuppaladadium Rathnam , Roy Anindya , Somnath Maji
Human cancer is a complex and highly diverse disease based on multiple aetiologies, multiple cell targets and distinct developmental stages. Notably, ruthenium-based complexes have emerged as good alternatives to traditional platinum-based drugs for cancer therapy. In this context, a mono and a dinuclear novel ruthenium(II) p-cymene complex formulated as [(p-cymene)Ru(L)Cl](PF6) and [(p-cymene)2Ru2(L)Cl2](PF6)2 (L = N-(3,5-di(pyridin-2-yl)-4H-1,2,4-triazol-4-yl)-1,8-naphthalimide) respectively have been synthesized and characterized by different spectroscopic techniques i.e., UV–vis, 1H NMR, 13C NMR, COSY, FT-IR and mass spectrometry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cyclic voltammetry has also been performed. In addition, cytotoxicity against cancer cell growth was examined using two human breast cancer cell lines, MDA-MB-231 and MCF-7. Both the complex exhibited strong DNA cleavage activity in vitro. However, cytotoxicity, cell viability and ROS production ability of [(p-cymene)2Ru2(L)Cl2](PF6)2 was found to be comparatively higher against triple negative breast cancer cell line MDA-MB-231.
{"title":"Cytotoxic evaluation of dinuclear ruthenium p-cymene complex with the mononuclear counterpart: A structural perspective","authors":"Anushka Verma , Arabinda Muley , Nafeesa Shahnaz , Sharan Shanmuga Vuppaladadium Rathnam , Roy Anindya , Somnath Maji","doi":"10.1016/j.jinorgbio.2026.113217","DOIUrl":"10.1016/j.jinorgbio.2026.113217","url":null,"abstract":"<div><div>Human cancer is a complex and highly diverse disease based on multiple aetiologies, multiple cell targets and distinct developmental stages. Notably, ruthenium-based complexes have emerged as good alternatives to traditional platinum-based drugs for cancer therapy. In this context, a mono and a dinuclear novel ruthenium(II) <em>p</em>-cymene complex formulated as [(<em>p</em>-cymene)Ru(<strong>L</strong>)Cl](PF<sub>6</sub>) and [(<em>p</em>-cymene)<sub>2</sub>Ru<sub>2</sub>(<strong>L</strong>)Cl<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> (<strong>L</strong> = N-(3,5-di(pyridin-2-yl)-4<em>H</em>-1,2,4-triazol-4-yl)-1,8-naphthalimide) respectively have been synthesized and characterized by different spectroscopic techniques <em>i.e.</em>, UV–vis, <sup>1</sup>H NMR, <sup>13</sup>C NMR, COSY, FT-IR and mass spectrometry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cyclic voltammetry has also been performed. In addition, cytotoxicity against cancer cell growth was examined using two human breast cancer cell lines, MDA-MB-231 and MCF-7. Both the complex exhibited strong DNA cleavage activity <em>in vitro</em>. However, cytotoxicity, cell viability and ROS production ability of [(<em>p</em>-cymene)<sub>2</sub>Ru<sub>2</sub>(<strong>L</strong>)Cl<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> was found to be comparatively higher against triple negative breast cancer cell line MDA-MB-231.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113217"},"PeriodicalIF":3.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964736","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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