Pub Date : 2026-06-01Epub Date: 2026-02-12DOI: 10.1016/j.jinorgbio.2026.113260
Oleg A. Zadvornyy , Mikhail Drobizhev , Monika Tokmina-Lukaszewska , Eric M. Shepard , William E. Broderick , Joan B. Broderick
Human radical S-adenosyl-l-methionine domain-containing 1 (hRSAD1) is a recently discovered mitochondrial protein that plays an important yet not fully understood role in cellular function. hRSAD1 belongs to the large and diverse radical S-adenosyl-l-methionine (SAM) superfamily of enzymes that utilize a redox-active [4Fe-4S] cluster and SAM to initiate radical catalysis. In addition, hRSAD1 harbors a putative heme-binding domain. hRSAD1 was expressed in E. coli and purified to homogeneity. The purified hRSAD1 was reconstituted with a [4Fe-4S]2+ cluster that could be reduced to the [4Fe-4S]+ state, and was characterized using UV–visible and EPR spectroscopy. The ability of hRSAD1 to bind porphyrins was evaluated, revealing that protoporphyrin IX (PPIX) and its metal analogs, including Fe(II)-PPIX, Fe(III)-PPIX, and Zn(II)-PPIX, bind to the reconstituted hRSAD1-[4Fe-4S] protein. The association constant (KA) for Fe(III)-PPIX was determined using UV–visible and fluorescence spectroscopy to be (1.6 ± 0.3) × 106 M−1. Additionally, the hRSAD1–[4Fe-4S]–heme complex binds oxygen, carbon monoxide, and cyanide. These findings suggest that hRSAD1 may play a significant role in heme-related metabolic processes.
{"title":"Human radical S-adenosylmethionine domain-containing 1 (RSAD1) is a Heme-binding protein","authors":"Oleg A. Zadvornyy , Mikhail Drobizhev , Monika Tokmina-Lukaszewska , Eric M. Shepard , William E. Broderick , Joan B. Broderick","doi":"10.1016/j.jinorgbio.2026.113260","DOIUrl":"10.1016/j.jinorgbio.2026.113260","url":null,"abstract":"<div><div>Human radical <em>S</em>-adenosyl-<span>l</span>-methionine domain-containing 1 (hRSAD1) is a recently discovered mitochondrial protein that plays an important yet not fully understood role in cellular function. hRSAD1 belongs to the large and diverse radical <em>S</em>-adenosyl-<span>l</span>-methionine (SAM) superfamily of enzymes that utilize a redox-active [4Fe-4S] cluster and SAM to initiate radical catalysis. In addition, hRSAD1 harbors a putative heme-binding domain. hRSAD1 was expressed in <em>E. coli</em> and purified to homogeneity. The purified hRSAD1 was reconstituted with a [4Fe-4S]<sup>2+</sup> cluster that could be reduced to the [4Fe-4S]<sup>+</sup> state, and was characterized using UV–visible and EPR spectroscopy. The ability of hRSAD1 to bind porphyrins was evaluated, revealing that protoporphyrin IX (PPIX) and its metal analogs, including Fe<sup>(II)</sup>-PPIX, Fe<sup>(III)</sup>-PPIX, and Zn<sup>(II)</sup>-PPIX, bind to the reconstituted hRSAD1-[4Fe-4S] protein. The association constant (K<sub>A</sub>) for Fe<sup>(III)</sup>-PPIX was determined using UV–visible and fluorescence spectroscopy to be (1.6 ± 0.3) × 10<sup>6</sup> M<sup>−1</sup>. Additionally, the hRSAD1–[4Fe-4S]–heme complex binds oxygen, carbon monoxide, and cyanide. These findings suggest that hRSAD1 may play a significant role in heme-related metabolic processes.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113260"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300732","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 : 2026-06-01Epub Date: 2026-02-20DOI: 10.1016/j.jinorgbio.2026.113267
Erica J. Peterson, Nicholas P. Farrell
This brief review summarizes our work showing that glycosaminoglycans (GAGs) are mediators of platinum complex cellular accumulation. Especially, there is an inverse relationship whereby charged polynuclear platinum complexes exemplified by BBR3464 and BBR3571 show enhanced tumor accumulation and antitumor efficacy in presence of a high level of GAGs whereas the inverse relationship occurs for the neutral mononuclear carboplatin. These results add to our understanding of the tumor uptake of platinum anticancer drugs and suggest avenues toward precision medicine for platinums based on patient stratification.
{"title":"Selective tumor accumulation as a route to precision medicine for platinum anticancer drugs","authors":"Erica J. Peterson, Nicholas P. Farrell","doi":"10.1016/j.jinorgbio.2026.113267","DOIUrl":"10.1016/j.jinorgbio.2026.113267","url":null,"abstract":"<div><div>This brief review summarizes our work showing that glycosaminoglycans (GAGs) are mediators of platinum complex cellular accumulation. Especially, there is an inverse relationship whereby charged polynuclear platinum complexes exemplified by BBR3464 and BBR3571 show enhanced tumor accumulation and antitumor efficacy in presence of a high level of GAGs whereas the inverse relationship occurs for the neutral mononuclear carboplatin. These results add to our understanding of the tumor uptake of platinum anticancer drugs and suggest avenues toward precision medicine for platinums based on patient stratification.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113267"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147315954","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 : 2026-06-01Epub Date: 2026-02-09DOI: 10.1016/j.jinorgbio.2026.113261
Joseph Wang, Callum A. Rosser, Todd E. Markham, Rachel Codd
The recombinant Salinispora tropica CNB-440 siderophore synthetase StDesD catalysed the assembly of pools of hydroxamic acid-containing chelators from a set of linear, non-native substrates containing internal polyethylene glycol (PEG)n spacer units. The internal (PEG)n units were capped at each end by an equivalent of the native StDesD substrate N-hydroxy-N-succinyl-cadaverine (HSC, 1) to give the length-modulated substrate set 1-(PEG)n-1-L (n = 1–6) (12.1–12.6). Chemoenzymatic reactions analysed by liquid chromatography-mass spectrometry showed StDesD catalysed end-to-end condensation reactions of 12.1–12.6 producing the cognate dihydroxamic acid macrocycles 1-(PEG)n-1-MC (13.1–13.6) as major products. Minor amounts of the macrocycle using a (1)2-L substrate with no PEG insert was observed, showing the flexible PEG linker in 12.1–12.6 improved positioning of the reactive termini in the StDesD active site to promote condensation. The major product using (1)2-L was instead the tetrahydroxamic acid macrocycle (1)4-MC desferrioxamine T1 (DFOT1, 7) formed from the sufficiently flexible precursor (1)4-L desferrioxamine S1 (DFOS1, 4). Reaction mixtures incubated with Ga(III) produced 1:1 Ga(III)-13.1–13.6 complexes. The work demonstrates chemoenzymatic synthesis as a facile approach to assemble structurally diverse and functional chelators alongside providing mechanistic insight of siderophore synthetases.
{"title":"Hydroxamic acid chelator profiles and Ga(III) complexes from siderophore synthetase-mediated synthesis using length-modulated substrates","authors":"Joseph Wang, Callum A. Rosser, Todd E. Markham, Rachel Codd","doi":"10.1016/j.jinorgbio.2026.113261","DOIUrl":"10.1016/j.jinorgbio.2026.113261","url":null,"abstract":"<div><div>The recombinant <em>Salinispora tropica</em> CNB-440 siderophore synthetase <em>St</em>DesD catalysed the assembly of pools of hydroxamic acid-containing chelators from a set of linear, non-native substrates containing internal polyethylene glycol (PEG)<sub><em>n</em></sub> spacer units. The internal (PEG)<sub><em>n</em></sub> units were capped at each end by an equivalent of the native <em>St</em>DesD substrate <em>N</em>-hydroxy-<em>N</em>-succinyl-cadaverine (HSC, <strong>1</strong>) to give the length-modulated substrate set <strong>1</strong>-(PEG)<sub><em>n</em></sub>-<strong>1</strong>-L (<em>n</em> = 1–6) (<strong>12.1</strong>–<strong>12.6</strong>). Chemoenzymatic reactions analysed by liquid chromatography-mass spectrometry showed <em>St</em>DesD catalysed end-to-end condensation reactions of <strong>12.1</strong>–<strong>12.6</strong> producing the cognate dihydroxamic acid macrocycles <strong>1</strong>-(PEG)<sub><em>n</em></sub>-<strong>1</strong>-MC (<strong>13.1</strong>–<strong>13.6</strong>) as major products. Minor amounts of the macrocycle using a (<strong>1</strong>)<sub>2</sub>-L substrate with no PEG insert was observed, showing the flexible PEG linker in <strong>12.1</strong>–<strong>12.6</strong> improved positioning of the reactive termini in the <em>St</em>DesD active site to promote condensation. The major product using (<strong>1</strong>)<sub>2</sub>-L was instead the tetrahydroxamic acid macrocycle (<strong>1</strong>)<sub>4</sub>-MC desferrioxamine T<sub>1</sub> (DFOT<sub>1</sub>, <strong>7</strong>) formed from the sufficiently flexible precursor (<strong>1</strong>)<sub>4</sub>-L desferrioxamine S<sub>1</sub> (DFOS<sub>1</sub>, <strong>4</strong>). Reaction mixtures incubated with Ga(III) produced 1:1 Ga(III)-<strong>13.1</strong>–<strong>13.6</strong> complexes. The work demonstrates chemoenzymatic synthesis as a facile approach to assemble structurally diverse and functional chelators alongside providing mechanistic insight of siderophore synthetases.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113261"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211680","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 : 2026-06-01Epub Date: 2026-02-05DOI: 10.1016/j.jinorgbio.2026.113259
Theodore M. Present , Joan Selverstone Valentine , Jena E. Johnson , Robert K. Szilagyi
Iron‑sulfur clusters are enzyme cofactors essential to life and are proposed to form the basis of earliest metabolisms. Fe–S rhomb and cubane clusters require both Fe(II) and Fe(III) for stability, but the Archean ocean was dominated by reduced Fe(II). We hypothesize that protons could have served as an oxidant of Fe(II) to Fe(III) during cluster assembly. Concomitantly, coordinating ligands that complete the tetrahedral geometry of the iron sites in the molecular cubane clusters may have assured cluster stability and facilitated proton reduction. Density functional theory calculations suggest that protons delivered by H3O+, Fe(SH)+, or H2S can oxidize [2Fe–2S] clusters and promote the formation of cationic [4Fe–4S] clusters. The relative energetics of mackinawite-like (FeS)n(aq) neutral nanoparticle sheets and ligated cationic [4Fe–4S] cubanes further indicate that ligands, such as water, bisulfide, and bioligands (such as short peptides) indeed play a key role in trapping cubane cluster states along the process of mackinawite-like nanoparticle sheet formation. Together, the redox reaction by protons and ligand coordination could have enabled molecular Fe–S cluster cofactor assembly directly from the Fe(II)-rich, sulfide-bearing waters of early Earth.
{"title":"Formation and spontaneous oxidation of neutral [4Fe–4S] clusters in prebiotic oceans","authors":"Theodore M. Present , Joan Selverstone Valentine , Jena E. Johnson , Robert K. Szilagyi","doi":"10.1016/j.jinorgbio.2026.113259","DOIUrl":"10.1016/j.jinorgbio.2026.113259","url":null,"abstract":"<div><div>Iron‑sulfur clusters are enzyme cofactors essential to life and are proposed to form the basis of earliest metabolisms. Fe–S rhomb and cubane clusters require both Fe(II) and Fe(III) for stability, but the Archean ocean was dominated by reduced Fe(II). We hypothesize that protons could have served as an oxidant of Fe(II) to Fe(III) during cluster assembly. Concomitantly, coordinating ligands that complete the tetrahedral geometry of the iron sites in the molecular cubane clusters may have assured cluster stability and facilitated proton reduction. Density functional theory calculations suggest that protons delivered by H<sub>3</sub>O<sup>+</sup>, Fe(SH)<sup>+</sup>, or H<sub>2</sub>S can oxidize [2Fe–2S] clusters and promote the formation of cationic [4Fe–4S] clusters. The relative energetics of mackinawite-like (FeS)<sub>n</sub>(aq) neutral nanoparticle sheets and ligated cationic [4Fe–4S] cubanes further indicate that ligands, such as water, bisulfide, and bioligands (such as short peptides) indeed play a key role in trapping cubane cluster states along the process of mackinawite-like nanoparticle sheet formation. Together, the redox reaction by protons and ligand coordination could have enabled molecular Fe–S cluster cofactor assembly directly from the Fe(II)-rich, sulfide-bearing waters of early Earth.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113259"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300753","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 : 2026-06-01Epub Date: 2026-02-14DOI: 10.1016/j.jinorgbio.2026.113263
Hazrat Bilal , Cai-Xiang Zhang , Huichao Lin , Muhammad Nawaz Tahir , Muhammad Raza Shah , Sukanya Dej-adisai , Yu-He Liu , Yanghan Liu , Zhen-Feng Chen
Six zinc(II) carboxylate complexes were synthesized under reflux reactions and thoroughly characterized by single crystal X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and elemental analysis. They adopt to two general formulas: mononuclear [Zn(DPAA)2(H2O)2] (1) and binuclear [Zn₂(DPAA)4(L)2] (2–6), where DPAA = diphenyl acetate anion and L represents an ancillary ligand. L used are pyridine (py, 2), 2-chloropyridine (2-chloro-py, 3), 2-methylpyridine (2-methyl-py, 4), 2-aminopyidine (2-amino-py, 5), and 4,7-diphenyl-1,10-phenthroline (dip-phen, 6). Complex 1 exhibits a distorted octahedral geometry, whereas complexes 2–5 are binuclear with a distorted square pyramidal coordination environment; complex 6 also displays a distorted square pyramidal geometry. Antimicrobial assays against staphylococcus aureus (S. aureus) and other selected strains revealed minimum inhibitory concentrations (MICs) values of 300–1617.6 μM for free ligands and 0.9–1374.5 μM for complexes 1–6. Notably complexes 2, 4 and 5 exhibited stronger in vitro antibiofilm activity and a more pronounced inhibitory effect on extracellular proteins (ECPs) of S. aureus at concentrations of 0.25–15 μg/mL compared to vancomycin and complex 1, 3, and 6.In vivo antibiofilm studies demonstrated that complexes 2, 4, and 5 effectively suppressed dental biofilm formation in a rat model and reduced α-hemolysin secretion, with no observable toxicity toward Wi38 and RAW 264.7 cells. Molecular docking analysis indicated that complexes 2, 4, and 5 engage in diverse binding interactions with biofilm-associated proteins (Baps). Taken together, these findings highlight the therapeutic potential of complexes 2, 4, and 5 in addressing bacterial infections and biofilm-associated challenges.
{"title":"Synthesis and structural characterization of zinc(II) carboxylate complexes with antibacterial and in vivo antibiofilm activities","authors":"Hazrat Bilal , Cai-Xiang Zhang , Huichao Lin , Muhammad Nawaz Tahir , Muhammad Raza Shah , Sukanya Dej-adisai , Yu-He Liu , Yanghan Liu , Zhen-Feng Chen","doi":"10.1016/j.jinorgbio.2026.113263","DOIUrl":"10.1016/j.jinorgbio.2026.113263","url":null,"abstract":"<div><div>Six zinc(II) carboxylate complexes were synthesized under reflux reactions and thoroughly characterized by single crystal X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and elemental analysis. They adopt to two general formulas: mononuclear [Zn(DPAA)<sub>2</sub>(H<sub>2</sub>O)<sub>2</sub>] (<strong>1</strong>) and binuclear [Zn₂(DPAA)<sub>4</sub>(L)<sub>2</sub>] (<strong>2</strong>–<strong>6</strong>), where DPAA = diphenyl acetate anion and L represents an ancillary ligand. L used are pyridine (py, <strong>2</strong>), 2-chloropyridine (2-chloro-py, <strong>3</strong>), 2-methylpyridine (2-methyl-py, <strong>4</strong>), 2-aminopyidine (2-amino-py, <strong>5</strong>), and 4,7-diphenyl-1,10-phenthroline (dip-phen, <strong>6</strong>). Complex <strong>1</strong> exhibits a distorted octahedral geometry, whereas complexes <strong>2</strong>–<strong>5</strong> are binuclear with a distorted square pyramidal coordination environment; complex <strong>6</strong> also displays a distorted square pyramidal geometry. Antimicrobial assays against <em>staphylococcus aureus</em> (<em>S. aureus</em>) and other selected strains revealed minimum inhibitory concentrations (MICs) values of 300–1617.6 μM for free ligands and 0.9–1374.5 μM for complexes <strong>1</strong>–<strong>6</strong>. Notably complexes <strong>2</strong>, <strong>4</strong> and <strong>5</strong> exhibited stronger <em>in vitro</em> antibiofilm activity and a more pronounced inhibitory effect on extracellular proteins (ECPs) of <em>S. aureus</em> at concentrations of 0.25–15 μg/mL compared to vancomycin and complex <strong>1</strong>, <strong>3</strong>, and <strong>6.</strong> <em>In vivo</em> antibiofilm studies demonstrated that complexes <strong>2</strong>, <strong>4</strong>, and <strong>5</strong> effectively suppressed dental biofilm formation in a rat model and reduced α-hemolysin secretion, with no observable toxicity toward Wi38 and RAW 264.7 cells. Molecular docking analysis indicated that complexes <strong>2</strong>, <strong>4</strong>, and <strong>5</strong> engage in diverse binding interactions with biofilm-associated proteins (Baps). Taken together, these findings highlight the therapeutic potential of complexes <strong>2</strong>, <strong>4</strong>, and <strong>5</strong> in addressing bacterial infections and biofilm-associated challenges.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113263"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281549","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 : 2026-06-01Epub Date: 2026-02-21DOI: 10.1016/j.jinorgbio.2026.113272
Luca Mazzei , Arundhati Paul , Michele Cianci , Andrea Pizzi , Giuseppe Resnati , Stefano Ciurli
Antimicrobial resistance is one of the most significant global health threats of the 21st century, demanding urgent strategies for the development of novel therapeutic approaches. Urease, a nickel-dependent enzyme absent in the human proteome, represents an attractive target for drug development because several urease-expressing bacterial pathogens play a critical role in pathogenesis. Alternative strategies, such as drug repurposing, are necessary to uncover the potential of antimicrobial molecules. In this context, the organo‑selenium compound Ebselen has shown promising urease-inhibitory properties, but its therapeutic application is limited by toxicity concerns. Ebsulfur, a sulfur analog of Ebselen, offers a potentially safer alternative. In this study, we evaluated three Ebsulfur derivatives for their ability to inhibit urease from Sporosarcina pasteurii and Canavalia ensiformis. Biochemical assays demonstrated that these compounds effectively inactivate both bacterial and plant urease in the low micromolar range. The X-ray crystal structures of Sporosarcina pasteurii urease co-crystallized with two of the derivatives, determined at 1.95–1.96 Å resolution, suggested a mechanism involving di‑sulfuration of the catalytically essential αCys322 residue. These findings provide insight into the potential of Ebsulfur derivatives as antimicrobial agents, addressing the persistent lack of progress in antibiotic development, and contribute to the development of alternative antimicrobial strategies targeting resistant pathogens.
{"title":"Structure-activity studies reveal efficient inactivation of urease by Ebsulfur-based compounds","authors":"Luca Mazzei , Arundhati Paul , Michele Cianci , Andrea Pizzi , Giuseppe Resnati , Stefano Ciurli","doi":"10.1016/j.jinorgbio.2026.113272","DOIUrl":"10.1016/j.jinorgbio.2026.113272","url":null,"abstract":"<div><div>Antimicrobial resistance is one of the most significant global health threats of the 21st century, demanding urgent strategies for the development of novel therapeutic approaches. Urease, a nickel-dependent enzyme absent in the human proteome, represents an attractive target for drug development because several urease-expressing bacterial pathogens play a critical role in pathogenesis. Alternative strategies, such as drug repurposing, are necessary to uncover the potential of antimicrobial molecules. In this context, the organo‑selenium compound Ebselen has shown promising urease-inhibitory properties, but its therapeutic application is limited by toxicity concerns. Ebsulfur, a sulfur analog of Ebselen, offers a potentially safer alternative. In this study, we evaluated three Ebsulfur derivatives for their ability to inhibit urease from <em>Sporosarcina pasteurii</em> and <em>Canavalia ensiformis</em>. Biochemical assays demonstrated that these compounds effectively inactivate both bacterial and plant urease in the low micromolar range. The X-ray crystal structures of <em>Sporosarcina pasteurii</em> urease co-crystallized with two of the derivatives, determined at 1.95–1.96 Å resolution, suggested a mechanism involving di‑sulfuration of the catalytically essential αCys322 residue. These findings provide insight into the potential of Ebsulfur derivatives as antimicrobial agents, addressing the persistent lack of progress in antibiotic development, and contribute to the development of alternative antimicrobial strategies targeting resistant pathogens.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113272"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368927","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 : 2026-06-01Epub Date: 2026-02-13DOI: 10.1016/j.jinorgbio.2026.113269
Deepika Verma , Sana Parveen , Mariyam Fatma , Kiran Gupta , Snober S. Mir , Om Prakash
Metal-based three positional isomeric, homoleptic Bi(III) dithiocarbamates [Bi{S2C-N(CH2Ph) (CH2-X-OH-C6H4)}3] (X = 2,3,4 Bi-2ba, Bi-3ba, and Bi-4ba respectively) named as tris[(N-benzyl-N-(X-hydroxybenzyl) dithiocarbamato-κ2S,S)] bismuth(III) were explored for anticancer activity using cancer cell A549. The complexes were characterized by infrared spectroscopy (IR), proton and carbon nuclear magnetic resonance spectroscopy (1H/13C{1H} NMR), ultraviolet-visible spectroscopy (UV–vis), and high-resolution mass spectrometry (HRMS). These characterization techniques confirmed the compositional integrity, solution stability over the experimental timeframe, and κ2 (S, S) chelation of the three dithiocarbamates(DTC) ligands at the Bi(III) center. Density functional theory (DFT) reveals that the isomers are essentially isostructural, giving a distorted pseudo-octahedral S6 environment around the Bi(III) center (BiS 2.76–2.84 A0, bite angle S-Bi-S 840, thioureide NC 1.34–1.35 A0). Cytotoxicity evaluation against A549 human lung carcinoma cells using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 24 h shows an isomer dependent potency trend Bi-4ba(10 μM) > Bi-3ba (20 μM) > Bi-2ba(60 μM); compared with 5-fluorouracil (5-FU) 20 μM under similar conditions. Mechanistic studies, including intracellular reactive oxygen species (ROS), mitochondrial membrane depolarization, and nuclear morphology visualized using 4′,6-diamidino-2-phenylindole (DAPI) staining, indicate oxidative stress mediated, mitochondria dependent apoptosis. These results indicate that positional isomerism-driven modulation of electronic structure correlates qualitatively with the observed cytotoxicity for A549.
{"title":"Synthesis, characterization, and DFT studies of isomeric homoleptic Bi (III) dithiocarbamate complexes vis-à-vis cytotoxicity in cancer cell, A549","authors":"Deepika Verma , Sana Parveen , Mariyam Fatma , Kiran Gupta , Snober S. Mir , Om Prakash","doi":"10.1016/j.jinorgbio.2026.113269","DOIUrl":"10.1016/j.jinorgbio.2026.113269","url":null,"abstract":"<div><div>Metal-based three positional isomeric, homoleptic Bi(III) dithiocarbamates [Bi{S<sub>2</sub>C-N(CH<sub>2</sub>Ph) (CH<sub>2</sub>-X-OH-C<sub>6</sub>H<sub>4</sub>)}<sub>3</sub>] (X = 2,3,4 Bi-2ba, Bi-3ba, and Bi-4ba respectively) named as tris[(N-benzyl-N-(X-hydroxybenzyl) dithiocarbamato-κ<sup>2</sup>S,S)] bismuth(III) were explored for anticancer activity using cancer cell A549. The complexes were characterized by infrared spectroscopy (IR), proton and carbon nuclear magnetic resonance spectroscopy (<sup>1</sup>H/<sup>13</sup>C{<sup>1</sup>H} NMR), ultraviolet-visible spectroscopy (UV–vis), and high-resolution mass spectrometry (HRMS). These characterization techniques confirmed the compositional integrity, solution stability over the experimental timeframe, and κ<sup>2</sup> (S, S) chelation of the three dithiocarbamates(DTC) ligands at the Bi(III) center. Density functional theory (DFT) reveals that the isomers are essentially isostructural, giving a distorted pseudo-octahedral S<sub>6</sub> environment around the Bi(III) center (Bi<img>S 2.76–2.84 A<sup>0</sup>, bite angle S-Bi-S 84<sup>0</sup>, thioureide N<img>C 1.34–1.35 A<sup>0</sup>). Cytotoxicity evaluation against A549 human lung carcinoma cells using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 24 h shows an isomer dependent potency trend Bi-4ba(10 μM) > Bi-3ba (20 μM) > Bi-2ba(60 μM); compared with 5-fluorouracil (5-FU) 20 μM under similar conditions. Mechanistic studies, including intracellular reactive oxygen species (ROS), mitochondrial membrane depolarization, and nuclear morphology visualized using 4′,6-diamidino-2-phenylindole (DAPI) staining, indicate oxidative stress mediated, mitochondria dependent apoptosis. These results indicate that positional isomerism-driven modulation of electronic structure correlates qualitatively with the observed cytotoxicity for A549.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113269"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211719","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 : 2026-06-01Epub Date: 2026-02-12DOI: 10.1016/j.jinorgbio.2026.113268
Salvatore La Gatta , Jacob K. Firby , James E. Penner-Hahn , Vincent L. Pecoraro
Anions such as halides and pseudohalides influence metal-site structure and function. De novo designed metallocoiled coils offer a defined platform for studying how metal centers recognize small anions within an α-helical scaffold. Spectroscopic examination of anion binding to three-stranded coiled coils (3SCCs) using artificial cobalt(II) substituted carbonic anhydrases (CA) is used as an analogue of the zinc(II) center. Scaffolds composed of three equivalents of GRW-H (Ac-GWKALEEKLKALEEKLKALEEKLKALEEKHKALEEKG-NH2) yield a cobalt(II)(His)3 site whose visible spectrum can be perturbed by nitrite, azide, and thiocyanate, producing significant ligand-field spectral changes that reveal these ions bind with millimolar affinities. These modifications reflect similar chemistry to that observed for cobalt(II)-substituted CA. X-ray absorption spectroscopy confirms that thiocyanate coordinates through nitrogen, converting a 6-coordinate cobalt(II)(His)3(H2O)3–x(OH−)x (with x = 0 or 1) species at pH ≤ 9 to a five-coordinate cobalt(II) center. pH-dependent measurements reveal a factor of 2 affinity increase for thiocyanate binding as solution basicity increases, with a pKa ∼ 8.0 consistent with a single deprotonation event. This strengthening of the binding constant does not arise from thiocyanic acid acidity or cobalt hydrolysis and likely reflects deprotonation of a protein residue(s). In contrast to thiocyanate or azide, halides (chloride through iodide) bind much more weakly. The spectral parameters observed vary with anion properties and reflect distinct cobalt(II) geometries. Overall, these results define how a simple His3 site embedded in a designed protein scaffold recognizes anions and adopts distinct geometries, providing a foundation for designing metalloproteins that activate small inorganic substrates.
{"title":"Probing anion recognition in a cobalt(II) de novo designed metalloprotein","authors":"Salvatore La Gatta , Jacob K. Firby , James E. Penner-Hahn , Vincent L. Pecoraro","doi":"10.1016/j.jinorgbio.2026.113268","DOIUrl":"10.1016/j.jinorgbio.2026.113268","url":null,"abstract":"<div><div>Anions such as halides and pseudohalides influence metal-site structure and function. <em>De novo</em> designed metallocoiled coils offer a defined platform for studying how metal centers recognize small anions within an α-helical scaffold. Spectroscopic examination of anion binding to three-stranded coiled coils (3SCCs) using artificial cobalt(II) substituted carbonic anhydrases (CA) is used as an analogue of the zinc(II) center. Scaffolds composed of three equivalents of GRW-H (Ac-GWKALEEKLKALEEKLKALEEKLKALEEKHKALEEKG-NH<sub>2</sub>) yield a cobalt(II)(His)<sub>3</sub> site whose visible spectrum can be perturbed by nitrite, azide, and thiocyanate, producing significant ligand-field spectral changes that reveal these ions bind with millimolar affinities. These modifications reflect similar chemistry to that observed for cobalt(II)-substituted <em>CA.</em> X-ray absorption spectroscopy confirms that thiocyanate coordinates through nitrogen, converting a 6-coordinate cobalt(II)(His)<sub>3</sub>(H<sub>2</sub>O)<sub>3–x</sub>(OH<sup>−</sup>)<sub>x</sub> (with x = 0 or 1) species at pH ≤ 9 to a five-coordinate cobalt(II) center. pH-dependent measurements reveal a factor of 2 affinity increase for thiocyanate binding as solution basicity increases, with a pKa ∼ 8.0 consistent with a single deprotonation event. This strengthening of the binding constant does not arise from thiocyanic acid acidity or cobalt hydrolysis and likely reflects deprotonation of a protein residue(s). In contrast to thiocyanate or azide, halides (chloride through iodide) bind much more weakly. The spectral parameters observed vary with anion properties and reflect distinct cobalt(II) geometries. Overall, these results define how a simple His<sub>3</sub> site embedded in a designed protein scaffold recognizes anions and adopts distinct geometries, providing a foundation for designing metalloproteins that activate small inorganic substrates.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113268"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224939","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 : 2026-06-01Epub Date: 2026-02-25DOI: 10.1016/j.jinorgbio.2026.113274
Yan Zhang , Liang Shao , Ziyi Wang , Xiaohua Fang , Xianpeng Zhang , Guorui Fu , Li Xu , Guanying Li , Xingqiang Lü
The propensity of antibiotics to provoke drug resistance in clinical applications, along with their low selectivity, has collectively contributed to the problem of antibiotic misuse, posing a major challenge in contemporary antibacterial therapy. To tackle this issue, we designed and synthesized three amphiphilic pyridine-modified iridium complexes [Ir(ppy)2(bpy-Py)]+Cl− (IrP), [Ir(dFppy)2(bpy-Py)]+Cl− (IrF) and [Ir(dpqx)2(bpy-Py)]+Cl− (Ir-X). All three complexes exhibited stronger bactericidal activity against Gram-negative E. coli, P. aeruginosa and A.baumannii than against Gram-positive S. aureus and E. faecalis. These three complexes selectively bound to Gram-negative pathogens over Gram-positive pathogens. Among them, Ir-X with increased lipophilicity (logP = 2.58) exhibited the most promising profile, and superior antibacterial efficacy. Mechanistic studies revealed that Ir-X combats E. coli through membrane disruption, ROS generation, and ATP depletion, collectively leading to bacterial death. In vivo experiments in a murine model of acute peritonitis demonstrated that Ir-X effectively suppresses E. coli infection without causing significant tissue damage, highlighting its potential as a therapeutic agent for treating Gram-negative bacterial infections.
{"title":"Pyridine-containing iridium complexes as gram-negative bacteria specific therapeutic agents with low resistance development","authors":"Yan Zhang , Liang Shao , Ziyi Wang , Xiaohua Fang , Xianpeng Zhang , Guorui Fu , Li Xu , Guanying Li , Xingqiang Lü","doi":"10.1016/j.jinorgbio.2026.113274","DOIUrl":"10.1016/j.jinorgbio.2026.113274","url":null,"abstract":"<div><div>The propensity of antibiotics to provoke drug resistance in clinical applications, along with their low selectivity, has collectively contributed to the problem of antibiotic misuse, posing a major challenge in contemporary antibacterial therapy. To tackle this issue, we designed and synthesized three amphiphilic pyridine-modified iridium complexes [Ir(ppy)<sub>2</sub>(bpy-Py)]<sup>+</sup>Cl<sup>−</sup> (Ir<img>P), [Ir(dFppy)<sub>2</sub>(bpy-Py)]<sup>+</sup>Cl<sup>−</sup> (Ir<img>F) and [Ir(dpqx)<sub>2</sub>(bpy-Py)]<sup>+</sup>Cl<sup>−</sup> (Ir-X). All three complexes exhibited stronger bactericidal activity against Gram-negative <em>E. coli</em>, <em>P. aeruginosa</em> and <em>A.baumannii</em> than against Gram-positive <em>S. aureus</em> and <em>E. faecalis</em>. These three complexes selectively bound to Gram-negative pathogens over Gram-positive pathogens. Among them, Ir-X with increased lipophilicity (log<em>P</em> = 2.58) exhibited the most promising profile, and superior antibacterial efficacy. Mechanistic studies revealed that Ir-X combats <em>E. coli</em> through membrane disruption, ROS generation, and ATP depletion, collectively leading to bacterial death. <em>In vivo</em> experiments in a murine model of acute peritonitis demonstrated that Ir-X effectively suppresses <em>E. coli</em> infection without causing significant tissue damage, highlighting its potential as a therapeutic agent for treating Gram-negative bacterial infections.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113274"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321126","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 : 2026-06-01Epub Date: 2026-02-13DOI: 10.1016/j.jinorgbio.2026.113270
Catarina Pimpão , Graça Soveral , Isabel Correia , João Costa Pessoa
Aquaporins (AQPs) are transmembrane proteins that facilitate the bidirectional transport of water, glycerol, and small solutes across cell membranes. AQPs are potential targets for drug development, namely for cancer treatment. In this work, we address the effect of several Cu-, Zn- and V-phen complexes on AQP1, which is selective for water transport, and AQP3, mainly involved in the transport of water and glycerol. A group of M(Xphen)22+ compounds (M = Cu2+, Zn2+, VIVO2+; Xphen = 1,10-phenanthroline, 5-amino-1,10-phenanthroline (Amphen), 4,7-dimethyl-1,10-phenanthroline), known to be cytotoxic agents against several human cancer-cell lines, were evaluated for their inhibitory effect of AQP1 and AQP3 by testing membrane water and glycerol permeability of human erythrocytes. In most cases, the inhibitory effects of the metal-complexes and those of the free Xphen compounds on the AQP1 and AQP3 permeability were not significantly different, suggesting that the effects are mostly due to the free Xphen compounds. The only exception is VIVO(Amphen)2(SO4), with an IC50 value of (9.11 ± 0.03 μM) in AQP1-mediated water permeation; this represents a promising compound for inhibition of AQP1, since until now there are no known potent and selective AQP1 inhibitors. At 100 μM, CuSO₄ slightly inhibited glycerol permeability, whereas ZnCl2, NaVVO3, and NH4VVO3 showed negligible effects. Speciation modelling indicates that hydrolysis and the formation of multiple metal-containing species occur under experimental conditions, except for Cu(Xphen)22+ complexes. These results highlight the importance of considering metal complex speciation in biological environments and suggest that encapsulation strategies may be required to preserve the integrity of labile metal complexes.
{"title":"The relevance of considering metal–ligand speciation in aquaporin modulation by cu, Zn, and V complexes with 1,10-phenanthroline ligands","authors":"Catarina Pimpão , Graça Soveral , Isabel Correia , João Costa Pessoa","doi":"10.1016/j.jinorgbio.2026.113270","DOIUrl":"10.1016/j.jinorgbio.2026.113270","url":null,"abstract":"<div><div>Aquaporins (AQPs) are transmembrane proteins that facilitate the bidirectional transport of water, glycerol, and small solutes across cell membranes. AQPs are potential targets for drug development, namely for cancer treatment. In this work, we address the effect of several Cu-, Zn- and V-phen complexes on AQP1, which is selective for water transport, and AQP3, mainly involved in the transport of water and glycerol. A group of M(Xphen)<sub>2</sub><sup>2+</sup> compounds (M = Cu<sup>2+</sup>, Zn<sup>2+</sup>, V<sup>IV</sup>O<sup>2+</sup>; Xphen = 1,10-phenanthroline, 5-amino-1,10-phenanthroline (Amphen), 4,7-dimethyl-1,10-phenanthroline), known to be cytotoxic agents against several human cancer-cell lines, were evaluated for their inhibitory effect of AQP1 and AQP3 by testing membrane water and glycerol permeability of human erythrocytes. In most cases, the inhibitory effects of the metal-complexes and those of the free Xphen compounds on the AQP1 and AQP3 permeability were not significantly different, suggesting that the effects are mostly due to the free Xphen compounds. The only exception is V<sup>IV</sup>O(Amphen)<sub>2</sub>(SO<sub>4</sub>), with an IC<sub>50</sub> value of (9.11 ± 0.03 μM) in AQP1-mediated water permeation; this represents a promising compound for inhibition of AQP1, since until now there are no known potent and selective AQP1 inhibitors. At 100 μM, CuSO₄ slightly inhibited glycerol permeability, whereas ZnCl<sub>2</sub>, NaV<sup>V</sup>O<sub>3</sub>, and NH<sub>4</sub>V<sup>V</sup>O<sub>3</sub> showed negligible effects. Speciation modelling indicates that hydrolysis and the formation of multiple metal-containing species occur under experimental conditions, except for Cu(Xphen)<sub>2</sub><sup>2+</sup> complexes. These results highlight the importance of considering metal complex speciation in biological environments and suggest that encapsulation strategies may be required to preserve the integrity of labile metal complexes.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113270"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211666","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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