Pub Date : 2026-06-01Epub Date: 2026-02-19DOI: 10.1016/j.jinorgbio.2026.113271
Chiara Ragusa , Roberta Panebianco , Vincenzo Paratore , Guglielmo Guido Condorelli , Kaveh Eskandari , Douglas Robinson , Fraser J. Scott , Rosanna Inturri , Maria Serena Rossitto , Valentina Giglio , Graziella Vecchio
The rise of antibiotic resistance necessitates the development of innovative strategies to enhance the effectiveness of existing treatments. One promising approach leverages bacterial iron acquisition systems through siderophore-based drug delivery to increase intracellular drug concentrations, a Trojan horse strategy. We synthesized new cyclodextrin conjugates with siderophores, such as deferoxamine and gallic acid, to exploit the cyclodextrin drug inclusion capability within the Trojan horse strategy. These novel derivatives were investigated as doxycycline carriers in the bacteria Escherichia coli and Staphylococcus aureus. Notably, the cyclodextrin deferoxamine derivative significantly enhanced the doxycycline efficacy by a 4-fold improvement of its minimal inhibitory concentration against Escherichia coli.
{"title":"Cyclodextrin–siderophore conjugates as a Trojan horse strategy for bacterial targeting","authors":"Chiara Ragusa , Roberta Panebianco , Vincenzo Paratore , Guglielmo Guido Condorelli , Kaveh Eskandari , Douglas Robinson , Fraser J. Scott , Rosanna Inturri , Maria Serena Rossitto , Valentina Giglio , Graziella Vecchio","doi":"10.1016/j.jinorgbio.2026.113271","DOIUrl":"10.1016/j.jinorgbio.2026.113271","url":null,"abstract":"<div><div>The rise of antibiotic resistance necessitates the development of innovative strategies to enhance the effectiveness of existing treatments. One promising approach leverages bacterial iron acquisition systems through siderophore-based drug delivery to increase intracellular drug concentrations, a Trojan horse strategy. We synthesized new cyclodextrin conjugates with siderophores, such as deferoxamine and gallic acid, to exploit the cyclodextrin drug inclusion capability within the Trojan horse strategy. These novel derivatives were investigated as doxycycline carriers in the bacteria <em>Escherichia coli</em> and <em>Staphylococcus aureus</em>. Notably, the cyclodextrin deferoxamine derivative significantly enhanced the doxycycline efficacy by a 4-fold improvement of its minimal inhibitory concentration against <em>Escherichia coli</em>.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113271"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269342","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: 2026-02-26DOI: 10.1016/j.jinorgbio.2026.113273
Peijie Liang , Lei Qi , Yongbin Chen, Mingyang Zhang, Yuting Luo, Zhihao Yang, Susu Li, Lihua Guo, Zhe Liu
To merge the intrinsic fluorescence and bioactivity of coumarin with the anticancer efficacy of Schiff base metal complexes, a series of half-sandwich Ir(III) and Ru(II) complexes bearing coumarin–salicylaldimine (N^O) ligands were designed and synthesized. The structures of the complexes were fully characterized, and their photoluminescent and biological properties were systematically investigated. These complexes exhibited adequate stability with slow hydrolysis and cytotoxicity comparable to that of cisplatin. The introduction of the coumarin group endowed the complexes with favorable photoluminescence, which facilitated the further investigation of their anticancer mechanism. Confocal microscopy revealed that the complexes enter cells via an energy-dependent pathway and preferentially accumulate in mitochondria. Consequently, they induce apoptosis by disrupting the mitochondrial membrane potential and generating excessive reactive oxygen species (ROS). In addition, the complexes interfere with the cell cycle, arresting cancer cells at the S or G0/G1 phase, and effectively inhibit cell migration in vitro.
{"title":"Integrating a fluorescent coumarin core into Schiff base half-sandwich Ir(III) or Ru(II) complexes for mitochondria-mediated anticancer activity","authors":"Peijie Liang , Lei Qi , Yongbin Chen, Mingyang Zhang, Yuting Luo, Zhihao Yang, Susu Li, Lihua Guo, Zhe Liu","doi":"10.1016/j.jinorgbio.2026.113273","DOIUrl":"10.1016/j.jinorgbio.2026.113273","url":null,"abstract":"<div><div>To merge the intrinsic fluorescence and bioactivity of coumarin with the anticancer efficacy of Schiff base metal complexes, a series of half-sandwich Ir(III) and Ru(II) complexes bearing coumarin–salicylaldimine (N<sup>^</sup>O) ligands were designed and synthesized. The structures of the complexes were fully characterized, and their photoluminescent and biological properties were systematically investigated. These complexes exhibited adequate stability with slow hydrolysis and cytotoxicity comparable to that of cisplatin. The introduction of the coumarin group endowed the complexes with favorable photoluminescence, which facilitated the further investigation of their anticancer mechanism. Confocal microscopy revealed that the complexes enter cells via an energy-dependent pathway and preferentially accumulate in mitochondria. Consequently, they induce apoptosis by disrupting the mitochondrial membrane potential and generating excessive reactive oxygen species (ROS). In addition, the complexes interfere with the cell cycle, arresting cancer cells at the S or G0/G1 phase, and effectively inhibit cell migration in vitro.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113273"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147363865","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.2026.113266
Yao Wu , Xuwen Da , Yunli Xu , Xiulian Liu , Aifeng Wu , Yu Shi , Xinyue Zou , Lingqing Yang , Xuesong Wang , Kun Wang , Qianxiong Zhou
Antibacterial photodynamic therapy (aPDT) represents a highly promising approach for combating resistant pathogens without inducing drug resistance. Selective photo-inactivation of bacteria without damage to the mammalian cells is a prerequisite for the clinical application of aPDT. In this work, based on the different azoreductase levels between mammalian cells and Staphylococcus aureus (S. aureus), an azoreductase-responsive “OFF-ON-OFF” photosensitizer, namely Ru-AzoCF3, was designed and synthesized as a proof-of-concept. The aPDT activity of Ru-AzoCF3 is initially suppressed by the presence of the azo group but can be activated by azoreductase, which is overexpressed in S. aureus. After exiting the bacterial cells, the activated photosensitizer reverts to an “OFF” state through a reversible “azo-hydrazine-azo” transformation, thereby precisely limiting the aPDT activity within pathogens and greatly minimize the potential phototoxicity to the mammalian cells. The detailed results demonstrated that Ru-AzoCF3 could selectively image and photo-inactivate S. aureus and methicillin-resistant S. aureus (MRSA) both in vitro and in vivo, surpassing the performance of vancomycin. This study may provide new insights for developing highly selective aPDT agents.
{"title":"An azoreductase-responsive “OFF-ON-OFF” reversible photosensitizer for highly selective antibacterial photodynamic therapy","authors":"Yao Wu , Xuwen Da , Yunli Xu , Xiulian Liu , Aifeng Wu , Yu Shi , Xinyue Zou , Lingqing Yang , Xuesong Wang , Kun Wang , Qianxiong Zhou","doi":"10.1016/j.jinorgbio.2026.113266","DOIUrl":"10.1016/j.jinorgbio.2026.113266","url":null,"abstract":"<div><div>Antibacterial photodynamic therapy (aPDT) represents a highly promising approach for combating resistant pathogens without inducing drug resistance. Selective photo-inactivation of bacteria without damage to the mammalian cells is a prerequisite for the clinical application of aPDT. In this work, based on the different azoreductase levels between mammalian cells and <em>Staphylococcus aureus</em> (<em>S. aureus</em>), an azoreductase-responsive “OFF-ON-OFF” photosensitizer, namely Ru-AzoCF<sub>3</sub>, was designed and synthesized as a proof-of-concept. The aPDT activity of Ru-AzoCF<sub>3</sub> is initially suppressed by the presence of the azo group but can be activated by azoreductase, which is overexpressed in <em>S. aureus</em>. After exiting the bacterial cells, the activated photosensitizer reverts to an “OFF” state through a reversible “azo-hydrazine-azo” transformation, thereby precisely limiting the aPDT activity within pathogens and greatly minimize the potential phototoxicity to the mammalian cells. The detailed results demonstrated that Ru-AzoCF<sub>3</sub> could selectively image and photo-inactivate <em>S. aureus</em> and methicillin-resistant <em>S. aureus</em> (MRSA) both <em>in vitro</em> and <em>in vivo</em>, surpassing the performance of vancomycin. This study may provide new insights for developing highly selective aPDT agents.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"279 ","pages":"Article 113266"},"PeriodicalIF":3.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218144","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 : 2026-05-01Epub 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":"2026-05-01","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 : 2026-05-01Epub Date: 2026-01-21DOI: 10.1016/j.jinorgbio.2026.113234
Dario B. Fortaleza , Josias S. Rocha , George B.S. Pereira , Tamara Teixeira , Jocely L. Dutra , Carlos A.F. Moraes , Pedro H.O. Santiago , Alzir A. Batista , Moacir R. Forim , Javier A. Ellena , Fillipe V. Rocha
Cancer remains one of the leading causes of death worldwide, with millions of new cases diagnosed annually. Cisplatin is a major advance in chemotherapy, but its severe side effects and the development of resistance limit its long-term effectiveness. In this context, palladium(II) complexes have gained attention as structural analogues of platinum compounds because they have the potential to exhibit antitumor activity while reducing toxicity. Six novel palladium(II) complexes containing thiosemicarbazide derivatives and diphosphine ligands [1,3-bis(diphenylphosphine)propane (dppp) or 1,4-bis(diphenylphosphine)butane (dppb)] were synthesized and thoroughly characterized by FTIR, 1H NMR and 31P NMR, high-resolution mass spectrometry, UV–Vis spectroscopy, and single-crystal X-ray diffraction. The structural analyses confirmed distorted square-planar Pd(II) geometries featuring N,S-bidentate thiosemicarbazide and chelating bisphosphine ligands. The cytotoxicity of the complexes was evaluated against breast (MCF-7 and MDA-MB-231), prostate (DU-145), lung (A549), ovarian (A2780 and A2780cis), and non-tumor (MRC-5) cell lines using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. One of the complexes exhibited the highest cytotoxicity, with IC₅₀ values approaching 1 μM in ovarian and breast cancer cells. B3 was about 25–30 times more active and selective than cisplatin (SI ≈ 15). Additional tests demonstrated that B3 blocked colony formation and migration, triggered dose-dependent apoptosis, and exhibited minimal toxicity to non-tumor cells. Notably, B3 demonstrated significant activity against cisplatin-resistant ovarian cells (A2780cis) in three-dimensional (3D) spheroid cultures, indicating its potential under physiologically relevant conditions. Overall, the structural features represent a promising lead compound for developing next-generation palladium-based metallodrugs with improved selectivity and effectiveness against resistant tumor types.
{"title":"Synthesis, structural characterization, and antitumor evaluation of Pd(II) Thiosemicarbazide–Diphosphine complexes in 2D and 3D cancer models","authors":"Dario B. Fortaleza , Josias S. Rocha , George B.S. Pereira , Tamara Teixeira , Jocely L. Dutra , Carlos A.F. Moraes , Pedro H.O. Santiago , Alzir A. Batista , Moacir R. Forim , Javier A. Ellena , Fillipe V. Rocha","doi":"10.1016/j.jinorgbio.2026.113234","DOIUrl":"10.1016/j.jinorgbio.2026.113234","url":null,"abstract":"<div><div>Cancer remains one of the leading causes of death worldwide, with millions of new cases diagnosed annually. Cisplatin is a major advance in chemotherapy, but its severe side effects and the development of resistance limit its long-term effectiveness. In this context, palladium(II) complexes have gained attention as structural analogues of platinum compounds because they have the potential to exhibit antitumor activity while reducing toxicity. Six novel palladium(II) complexes containing thiosemicarbazide derivatives and diphosphine ligands [1,3-bis(diphenylphosphine)propane (dppp) or 1,4-bis(diphenylphosphine)butane (dppb)] were synthesized and thoroughly characterized by FTIR, <sup>1</sup>H NMR and <sup>31</sup>P NMR, high-resolution mass spectrometry, UV–Vis spectroscopy, and single-crystal X-ray diffraction. The structural analyses confirmed distorted square-planar Pd(II) geometries featuring N,S-bidentate thiosemicarbazide and chelating bisphosphine ligands. The cytotoxicity of the complexes was evaluated against breast (MCF-7 and MDA-MB-231), prostate (DU-145), lung (A549), ovarian (A2780 and A2780cis), and non-tumor (MRC-5) cell lines using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. One of the complexes exhibited the highest cytotoxicity, with IC₅₀ values approaching 1 μM in ovarian and breast cancer cells. B3 was about 25–30 times more active and selective than cisplatin (SI ≈ 15). Additional tests demonstrated that B3 blocked colony formation and migration, triggered dose-dependent apoptosis, and exhibited minimal toxicity to non-tumor cells. Notably, B3 demonstrated significant activity against cisplatin-resistant ovarian cells (A2780cis) in three-dimensional (3D) spheroid cultures, indicating its potential under physiologically relevant conditions. Overall, the structural features represent a promising lead compound for developing next-generation palladium-based metallodrugs with improved selectivity and effectiveness against resistant tumor types.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113234"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The substitution of carboxylate donors with neutral amide groups is a well-established approach for tuning charge distribution and hydration properties in metal chelates; however, its influence on Fe(III) systems has remained largely unexplored. Here, we report two CDTA-derived ligands incorporating one or two secondary butylamide substituents (CD3A-BA and CD2A-BA₂) and comprehensively characterize their Fe(III) complexes using potentiometry, capillary zone electrophoresis, UV–Vis spectrophotometry, transchelation assays (with HBED and human serum transferrin), 1H NMRD, variable-temperature 17O NMR, and in vitro cytotoxicity tests. Amide incorporation decreases ligand basicity and leads to reduced complex stability and kinetic inertness compared to the parent CDTA framework. Nevertheless, the new Fe(III) complexes retain strong metal affinity and remain monohydrated under physiologically relevant conditions. Progressive amide substitution systematically slows inner-sphere water exchange, consistent with the higher residual positive charge of the complexes. Despite this, relaxivity in media mimicking physiological conditions remains unchanged, with negligible protein binding and no detectable Fe(III) release. Cellular assays confirm an absence of cytotoxicity at the tested concentrations. Collectively, these findings elucidate how secondary-amide substitution governs stability, reactivity, and hydration dynamics in Fe(III)–CDTA derivatives, offering valuable insights for the rational design of Fe(III)-based MRI contrast agents.
{"title":"Secondary amide derivatives of Fe(III)-CDTA: Impact of ligand substitution on relaxivity, stability, and kinetic inertness","authors":"M. Ludovica Macchia , Marco Ricci , Mariangela Boccalon , Zsolt Baranyai , Beatrice Ghezzi , Valentina Audrito , Mauro Botta","doi":"10.1016/j.jinorgbio.2026.113262","DOIUrl":"10.1016/j.jinorgbio.2026.113262","url":null,"abstract":"<div><div>The substitution of carboxylate donors with neutral amide groups is a well-established approach for tuning charge distribution and hydration properties in metal chelates; however, its influence on Fe(III) systems has remained largely unexplored. Here, we report two CDTA-derived ligands incorporating one or two secondary butylamide substituents (CD3A-BA and CD2A-BA₂) and comprehensively characterize their Fe(III) complexes using potentiometry, capillary zone electrophoresis, UV–Vis spectrophotometry, transchelation assays (with HBED and human serum transferrin), <sup>1</sup>H NMRD, variable-temperature <sup>17</sup>O NMR, and in vitro cytotoxicity tests. Amide incorporation decreases ligand basicity and leads to reduced complex stability and kinetic inertness compared to the parent CDTA framework. Nevertheless, the new Fe(III) complexes retain strong metal affinity and remain monohydrated under physiologically relevant conditions. Progressive amide substitution systematically slows inner-sphere water exchange, consistent with the higher residual positive charge of the complexes. Despite this, relaxivity in media mimicking physiological conditions remains unchanged, with negligible protein binding and no detectable Fe(III) release. Cellular assays confirm an absence of cytotoxicity at the tested concentrations. Collectively, these findings elucidate how secondary-amide substitution governs stability, reactivity, and hydration dynamics in Fe(III)–CDTA derivatives, offering valuable insights for the rational design of Fe(III)-based MRI contrast agents.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113262"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146185493","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 : 2026-05-01Epub Date: 2026-01-28DOI: 10.1016/j.jinorgbio.2026.113244
Isabel B. Calhau , Ana C. Gomes , Sofia M. Bruno , Fernanda Rosário , Laura Oliveira , Carla Pereira , Helena Oliveira , Adelaide Almeida , Isabel S. Gonçalves , Martyn Pillinger
Molybdenum-based CO-releasing molecules (CORMs) are attracting interest for biological and therapeutic applications. In this work two new complexes, [Mo(η3-C3H5)X(CO)2(Hpypz)] [X = Cl (1), Br (2); Hpypz = 3-(2-pyridyl)pyrazole] have been synthesized, characterized, and evaluated for their CO-release capacity, as well as antimicrobial and anticancer potential. The evaluation of the CO-release properties by the deoxymyoglobin‑carbonmonoxymyoglobin assay showed that the two complexes are comparably slow CO releasers in aqueous systems, showing a half-life of several hours, and sustained CO release over the course of the assay (6 h). Studies of biological activity were performed with complex 1 due to its better aqueous solubility. The antibacterial activity was investigated by determination of the minimum inhibitory and minimum bactericidal concentrations with the microdilution assay for gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative Escherichia coli strains. Complex 1 displayed appreciable concentration-dependent bactericidal activity against both strains. The cytotoxicity of complex 1 was evaluated on human melanoma cells (A375) and immortalized nontumorigenic keratinocytes (HaCaT). Complex 1 exhibited selective cytotoxicity, significantly reducing the cell viability of A375 cells in a dose-dependent manner while having a lower effect on HaCaT cells, suggesting its antitumor potential against melanoma. In contrast, the precursor complex [Mo(η3-C3H5)Cl(CO)2(CH3CN)2] showed reduced activity against A375 cells and higher toxicity toward HaCaT cells, highlighting the beneficial impact of the bidentate 3-(2-pyridyl)pyrazole ligand.
{"title":"Molybdenum(II) allyl dicarbonyl complexes with 3-(2-pyridyl)pyrazole as potential CO-releasing molecules, antibacterial and antitumoral agents","authors":"Isabel B. Calhau , Ana C. Gomes , Sofia M. Bruno , Fernanda Rosário , Laura Oliveira , Carla Pereira , Helena Oliveira , Adelaide Almeida , Isabel S. Gonçalves , Martyn Pillinger","doi":"10.1016/j.jinorgbio.2026.113244","DOIUrl":"10.1016/j.jinorgbio.2026.113244","url":null,"abstract":"<div><div>Molybdenum-based CO-releasing molecules (CORMs) are attracting interest for biological and therapeutic applications. In this work two new complexes, [Mo(<em>η</em><sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)X(CO)<sub>2</sub>(Hpypz)] [X = Cl (<strong>1</strong>), Br (<strong>2</strong>); Hpypz = 3-(2-pyridyl)pyrazole] have been synthesized, characterized, and evaluated for their CO-release capacity, as well as antimicrobial and anticancer potential. The evaluation of the CO-release properties by the deoxymyoglobin‑carbonmonoxymyoglobin assay showed that the two complexes are comparably slow CO releasers in aqueous systems, showing a half-life of several hours, and sustained CO release over the course of the assay (6 h). Studies of biological activity were performed with complex <strong>1</strong> due to its better aqueous solubility. The antibacterial activity was investigated by determination of the minimum inhibitory and minimum bactericidal concentrations with the microdilution assay for gram-positive methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) and gram-negative <em>Escherichia coli</em> strains. Complex <strong>1</strong> displayed appreciable concentration-dependent bactericidal activity against both strains. The cytotoxicity of complex <strong>1</strong> was evaluated on human melanoma cells (A375) and immortalized nontumorigenic keratinocytes (HaCaT). Complex <strong>1</strong> exhibited selective cytotoxicity, significantly reducing the cell viability of A375 cells in a dose-dependent manner while having a lower effect on HaCaT cells, suggesting its antitumor potential against melanoma. In contrast, the precursor complex [Mo(<em>η</em><sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)Cl(CO)<sub>2</sub>(CH<sub>3</sub>CN)<sub>2</sub>] showed reduced activity against A375 cells and higher toxicity toward HaCaT cells, highlighting the beneficial impact of the bidentate 3-(2-pyridyl)pyrazole ligand.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113244"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-02-01DOI: 10.1016/j.jinorgbio.2026.113246
Yibo Fu , Yungeun Lee , Daniel Kornitzer , Amit R. Reddi
Heme is an essential cofactor and nutritional source of iron for many pathogenic microbes, including the opportunistic fungal pathogen Candida albicans. C. albicans utilizes common fungal extracellular membrane (CFEM) domain containing hemophores to scavenge heme from the host and deliver it across the cell wall to the cell membrane, where is it subsequently internalized. Previous studies indicated that ferric reductase related proteins Frp1 and Frp2 were required for hemin transport and utilization. However, the molecular mechanism of Frp1 and Frp2 dependent heme uptake remains to be fully elucidated. Motivated by the similarity of Frp1 and Frp2 to ferric iron reductases, we sought to determine if Frp1/2 exhibited heme reductase activity and if heme‑iron oxidation state influenced its uptake in C. albicans. By utilizing ratiometric heme sensors, redox inactive fluorescent ferric and ferrous heme analogs, and a modified pyridine hemochrome method, we determined that C. albicans has a preference for transporting ferrous heme over ferric heme and exhibits cell surface heme reductase activity that is in part dependent on Frp1 and Frp2. Our results are the first to directly demonstrate C. albicans has the capacity to reduce extracellular heme‑iron and that its oxidation state may be important for heme uptake. We further found that another yeast species, Saccharomyces cerevisiae, which poorly utilizes heme iron, also exhibits heme reductase activity, pointing to the broader presence of extracellular heme reduction in the microbial world.
{"title":"Ferric reductase related proteins Frp1 and Frp2 mediate reductive heme uptake in the opportunistic pathogen Candida albicans","authors":"Yibo Fu , Yungeun Lee , Daniel Kornitzer , Amit R. Reddi","doi":"10.1016/j.jinorgbio.2026.113246","DOIUrl":"10.1016/j.jinorgbio.2026.113246","url":null,"abstract":"<div><div>Heme is an essential cofactor and nutritional source of iron for many pathogenic microbes, including the opportunistic fungal pathogen <em>Candida albicans</em>. <em>C. albicans</em> utilizes common fungal extracellular membrane (CFEM) domain containing hemophores to scavenge heme from the host and deliver it across the cell wall to the cell membrane, where is it subsequently internalized. Previous studies indicated that ferric reductase related proteins Frp1 and Frp2 were required for hemin transport and utilization. However, the molecular mechanism of Frp1 and Frp2 dependent heme uptake remains to be fully elucidated. Motivated by the similarity of Frp1 and Frp2 to ferric iron reductases, we sought to determine if Frp1/2 exhibited heme reductase activity and if heme‑iron oxidation state influenced its uptake in <em>C. albicans</em>. By utilizing ratiometric heme sensors, redox inactive fluorescent ferric and ferrous heme analogs, and a modified pyridine hemochrome method, we determined that <em>C. albicans</em> has a preference for transporting ferrous heme over ferric heme and exhibits cell surface heme reductase activity that is in part dependent on Frp1 and Frp2. Our results are the first to directly demonstrate <em>C. albicans</em> has the capacity to reduce extracellular heme‑iron and that its oxidation state may be important for heme uptake. We further found that another yeast species, <em>Saccharomyces cerevisiae</em>, which poorly utilizes heme iron, also exhibits heme reductase activity, pointing to the broader presence of extracellular heme reduction in the microbial world.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113246"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177130","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}
The Pt(II) and Pd(II) complexes with 1,10-phenanthroline derivative ligands, [Pt(L)(py)2](PF6)2 and [Pd(L)(py)2](PF6)2 (L = dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 10,11,12,13-tetrahydrodipyrido[3,2-a:2′,3′-c]phenazine (thdppz)), were synthesized, and their interactions with calf thymus DNA (ct-DNA) and anticancer activities against A549 cells (adenocarcinoma of the lung) were investigated. The electronic states and chemical properties (e.g., the stability in aqueous solution) of these Pt and Pd complexes were very similar to each other; however, their interactions with biomolecules such as DNA and bovine serum albumin differed substantially. From the ESI-MS data of each complex with guanosine, guanosine adducts of both Pd complexes were observed, while no guanosine adducts of the Pt complexes were observed. The CD and ESI-MS results suggested that [Pt(dppz)(py)2](PF6)2 interacts via intercalation, whereas [Pt(thdppz)(py)2](PF6)2 binds through electrostatic interactions. It was revealed that [Pd(dppz)(py)2](PF6)2 and [Pd(thdppz)(py)2](PF6)2 interact via a coordinate covalent bonding. Both Pd complexes exhibited strong cytotoxicity, although the Pt complexes showed no cytotoxicity. These results indicate that the anticancer activity of the Pd complexes strongly depends on their substitution activity. In addition, among the investigated complexes, [Pt(dppz)(py)2](PF6)2 is expected to be the most effective anticancer drug against cisplatin-resistant cancers because it interacts with ct-DNA through a different binding mode to that for cisplatin.
{"title":"Pt(II) and Pd(II) complexes bearing 1,10-phenanthroline-based ligands: Distinct binding modes to DNA and anticancer activities","authors":"Misaki Nakai , Yusuke Tsutsumi , Togo Imai , Tatsuo Yajima , Kazune Sano , Yasuo Nagaoka , Shigenobu Yano , Hitoshi Ishida","doi":"10.1016/j.jinorgbio.2026.113258","DOIUrl":"10.1016/j.jinorgbio.2026.113258","url":null,"abstract":"<div><div>The Pt(II) and Pd(II) complexes with 1,10-phenanthroline derivative ligands, [Pt(L)(py)<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> and [Pd(L)(py)<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> (L = dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 10,11,12,13-tetrahydrodipyrido[3,2-a:2′,3′-c]phenazine (thdppz)), were synthesized, and their interactions with calf thymus DNA (ct-DNA) and anticancer activities against A549 cells (adenocarcinoma of the lung) were investigated. The electronic states and chemical properties (e.g., the stability in aqueous solution) of these Pt and Pd complexes were very similar to each other; however, their interactions with biomolecules such as DNA and bovine serum albumin differed substantially. From the ESI-MS data of each complex with guanosine, guanosine adducts of both Pd complexes were observed, while no guanosine adducts of the Pt complexes were observed. The CD and ESI-MS results suggested that [Pt(dppz)(py)<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> interacts via intercalation, whereas [Pt(thdppz)(py)<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> binds through electrostatic interactions. It was revealed that [Pd(dppz)(py)<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> and [Pd(thdppz)(py)<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> interact via a coordinate covalent bonding. Both Pd complexes exhibited strong cytotoxicity, although the Pt complexes showed no cytotoxicity. These results indicate that the anticancer activity of the Pd complexes strongly depends on their substitution activity. In addition, among the investigated complexes, [Pt(dppz)(py)<sub>2</sub>](PF<sub>6</sub>)<sub>2</sub> is expected to be the most effective anticancer drug against cisplatin-resistant cancers because it interacts with ct-DNA through a different binding mode to that for cisplatin.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113258"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146185494","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 : 2026-05-01Epub Date: 2026-01-22DOI: 10.1016/j.jinorgbio.2026.113242
Zhiheng Wang, Yiwen Wang, Ivan J. Dmochowski
Studies of ferritin biomineralization have elucidated iron loading/egress pathways and mechanisms of iron oxidation, while paying less attention to the spatiotemporal details of proton generation during iron hydrolysis. Here, we performed ferroxidase reactions with Archaeoglobus fulgidus ferritin (AfFtn) 24mer cage, which allows site-specific labeling as a dimer at low ionic strength and reassembly into a 24mer at high ionic strength. Cysteines engineered on the ferritin interior surface were covalently labeled with fluorescein-5-maleimide (F5M), which reported the dynamic changes in proton activity during ferroxidase chemistry. F5M labeled at D61C was highly responsive to proton generation and release, without being vulnerable to fluorescence quenching by Fe2+/3+. C61-F5M fluorescence quenching was maximal within 15 s of stoichiometric Fe2+ addition, and corresponded to an apparent pH value of 5.5 in the cavity. C61-F5M recovered ∼25% of the original “pre‑iron” fluorescence signal on the 5-min timescale but did not recover further with longer incubation. A complementary fluorescein-labeled peptide in bulk solution showed immediate fluorescence quenching, consistent with direct proton release from the ferroxidase center. Solution pH measurements revealed additional acidification on the 5-min timescale, consistent with the kinetics of proton egress from the ferritin cavity. The external and internal pH probes indicated that ferritin releases into solution a total of 1.6H+ for each Fe2+ oxidation, while retaining 0.4H+. This agrees with prior measurements of 2 total H+ per Fe2+ oxidation, and now reveals ferritin's propensity to accumulate protons within the protein cavity, which serves as a “brake” on iron biomineralization.
{"title":"Cavity acidification limits ferritin iron biomineralization","authors":"Zhiheng Wang, Yiwen Wang, Ivan J. Dmochowski","doi":"10.1016/j.jinorgbio.2026.113242","DOIUrl":"10.1016/j.jinorgbio.2026.113242","url":null,"abstract":"<div><div>Studies of ferritin biomineralization have elucidated iron loading/egress pathways and mechanisms of iron oxidation, while paying less attention to the spatiotemporal details of proton generation during iron hydrolysis. Here, we performed ferroxidase reactions with <em>Archaeoglobus fulgidus</em> ferritin (AfFtn) 24mer cage, which allows site-specific labeling as a dimer at low ionic strength and reassembly into a 24mer at high ionic strength. Cysteines engineered on the ferritin interior surface were covalently labeled with fluorescein-5-maleimide (F5M), which reported the dynamic changes in proton activity during ferroxidase chemistry. F5M labeled at D61C was highly responsive to proton generation and release, without being vulnerable to fluorescence quenching by Fe<sup>2+</sup>/<sup>3+</sup>. C61-F5M fluorescence quenching was maximal within 15 s of stoichiometric Fe<sup>2+</sup> addition, and corresponded to an apparent pH value of 5.5 in the cavity. C61-F5M recovered ∼25% of the original “pre‑iron” fluorescence signal on the 5-min timescale but did not recover further with longer incubation. A complementary fluorescein-labeled peptide in bulk solution showed immediate fluorescence quenching, consistent with direct proton release from the ferroxidase center. Solution pH measurements revealed additional acidification on the 5-min timescale, consistent with the kinetics of proton egress from the ferritin cavity. The external and internal pH probes indicated that ferritin releases into solution a total of 1.6H<sup>+</sup> for each Fe<sup>2+</sup> oxidation, while retaining 0.4H<sup>+</sup>. This agrees with prior measurements of 2 total H<sup>+</sup> per Fe<sup>2+</sup> oxidation, and now reveals ferritin's propensity to accumulate protons within the protein cavity, which serves as a “brake” on iron biomineralization.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"278 ","pages":"Article 113242"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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