Pub Date : 2026-03-09DOI: 10.1016/j.jinorgbio.2026.113300
Kinga Garstka-Litwin, Magdalena Rowińska-Żyrek
Escalating resistance among bacterial and fungal pathogens calls for new therapeutic strategies that go beyond classical small-molecule antibiotics. Antimicrobial peptides (AMPs) are attractive candidates because they can act through multiple mechanisms and often evade conventional resistance pathways. Biologically essential metal ions such as Zn(II) and Cu(II) further expand this chemical space: metal binding can modulate peptide structure, morphology, local charge and transport, thereby generating metallo-AMPs with distinct modes of action. In this review, we discuss selected Zn(II)- and Cu(II)-binding AMPs and peptidic zincophores in which the link between coordination chemistry and biological activity has been analysed in detail. Rather than simply listing examples, we use these systems to show how a coherent research programme in bioinorganic AMP chemistry can be built around one guiding idea: connecting metal coordination to function across different peptide families. Pramlintide and shepherins illustrate Zn(II)-driven conformational change and fibril formation associated with antifungal activity. Semenogelins and calcitermin highlight how histidine-rich motifs and local charge tuning can activate peptides without relying on nutritional immunity. Clavanins reveal a "chemical butterfly effect", where subtle differences in pre-organization translate into changes in complex lability and antimicrobial outcome. Histatin systems show that metal-dependent effects can be strongly pH-gated. Finally, thermodynamic and structural studies of fungal zincophores and bacterial periplasmic transporters provide a basis for targeted peptide designs that exploit Zn(II) uptake pathways. Together, these case studies outline mechanism-based design principles for future metal-peptide therapeutics.
{"title":"Metal-tuned antimicrobial peptides and zincophore pathways: from coordination chemistry to targeted therapeutics.","authors":"Kinga Garstka-Litwin, Magdalena Rowińska-Żyrek","doi":"10.1016/j.jinorgbio.2026.113300","DOIUrl":"https://doi.org/10.1016/j.jinorgbio.2026.113300","url":null,"abstract":"<p><p>Escalating resistance among bacterial and fungal pathogens calls for new therapeutic strategies that go beyond classical small-molecule antibiotics. Antimicrobial peptides (AMPs) are attractive candidates because they can act through multiple mechanisms and often evade conventional resistance pathways. Biologically essential metal ions such as Zn(II) and Cu(II) further expand this chemical space: metal binding can modulate peptide structure, morphology, local charge and transport, thereby generating metallo-AMPs with distinct modes of action. In this review, we discuss selected Zn(II)- and Cu(II)-binding AMPs and peptidic zincophores in which the link between coordination chemistry and biological activity has been analysed in detail. Rather than simply listing examples, we use these systems to show how a coherent research programme in bioinorganic AMP chemistry can be built around one guiding idea: connecting metal coordination to function across different peptide families. Pramlintide and shepherins illustrate Zn(II)-driven conformational change and fibril formation associated with antifungal activity. Semenogelins and calcitermin highlight how histidine-rich motifs and local charge tuning can activate peptides without relying on nutritional immunity. Clavanins reveal a \"chemical butterfly effect\", where subtle differences in pre-organization translate into changes in complex lability and antimicrobial outcome. Histatin systems show that metal-dependent effects can be strongly pH-gated. Finally, thermodynamic and structural studies of fungal zincophores and bacterial periplasmic transporters provide a basis for targeted peptide designs that exploit Zn(II) uptake pathways. Together, these case studies outline mechanism-based design principles for future metal-peptide therapeutics.</p>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":" ","pages":"113300"},"PeriodicalIF":3.2,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479283","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 : 2026-03-06DOI: 10.1016/j.jinorgbio.2026.113292
Rupal Baliyan, Alejandro Javier Castillo, Brett N Schneider, Sudarshan Sharma, R Lee Penn, Gwendolyn A Bailey
The electronic states of iron‑sulfur (Fe-S) clusters in metalloenzymes are critically influenced by second and outer-sphere interactions-electrostatics, hydrogen bonding, and hydrophobic contacts-that modulate cofactor redox potentials and reactivity in processes ranging from cellular respiration to nitrogen fixation. To systematically probe these effects in a well-defined synthetic environment, we previously developed host-guest complexes of [Fe4S4(SR)4]2- clusters ([1R]2-, R = Ph, -CH2CH2OH) encapsulated within naphthalenediimide (NDI)-functionalized metal-organic cages [M4L6]8+ (M = Fe, Ni, Zn; L = organic linker), demonstrating that encapsulation substantially alters cluster electronic structure. Herein, we quantitatively dissect the individual contributions from second and outer-sphere electrostatics, π-π stacking, hydrogen bonding, and magnetic coupling. By investigating the host-guest series in two charge states, 1R⊂[Ni4L6]6+ and the reduced 1R⊂[Ni4L6]0 framework featuring [NDI]•- radical panels, we isolate the specific influence of the host's electronic environment on the guest cofactors. As controls, we examine the free clusters and unencapsulated ion pairs [Ni4L6][1tBu]6+ and [Ni4L6][1tBu], for which encapsulation is precluded by weak interfacial interactions and the smaller size of [1tBu]2-. In-depth Fe 2p X-ray photoelectron, infrared, and UV-visible spectroscopic analysis establishes substantial changes in binding energy and Fe-S bond covalency, with contributions from electrostatic stabilization (+0.6 eV binding energy shift) and second-sphere π-stacking/hydrogen bonding (+0.3 - 0.5 eV). Meanwhile, analysis of reduced congeners [Ni4L6]2+, 1R⊂[Ni4L6], and [Ni4L6][1tBu] enables dissection of subtle magnetic effects arising from cofactor association with the [NDI]•- cage. These findings establish supramolecular cages as a platform for deconvoluting second and outer-sphere effects on iron‑sulfur cofactor electronic structure and redox activity--.
金属酶中铁硫（Fe-S）簇的电子态受到第二球和外球相互作用（静电、氢键和疏水接触）的严重影响，这些相互作用调节从细胞呼吸到固氮等过程中的辅因子氧化还原电位和反应性。为了在一个明确的合成环境中系统地探测这些影响，我们之前开发了主客体配合物[Fe4S4(SR)4]2-簇（[1R]2-, R = Ph, - ch2ch2oh）包裹在naphthalenedi亚胺（NDI）功能化金属-有机笼[M4L6]8+ （M = Fe, Ni, Zn; L =有机连接剂）中，证明了包封实质上改变了簇的电子结构。在这里，我们定量地分析了第二球和外球静电、π-π堆叠、氢键和磁耦合的个别贡献。通过研究两种电荷状态下的主客系列，即1R∧[Ni4L6]6+和具有[NDI]•自由基面板的简化1R∧[Ni4L6]0框架，我们隔离了主电子环境对客辅因子的具体影响。作为对照，我们研究了自由簇和未封装离子对[Ni4L6][1tBu]6+和[Ni4L6][1tBu]6+和[Ni4L6][1tBu]，它们的封装由于弱界面相互作用和[1tBu]2-的较小尺寸而被排除。深入的Fe 2p x射线光电子、红外和紫外可见光谱分析发现，Fe- s键的结合能和共价发生了实质性的变化，这主要得益于静电稳定（+0.6 eV结合能位移）和第二球π堆积/氢键（+0.3 - 0.5 eV）。同时，通过对还原同族[Ni4L6]2+、[Ni4L6]和[Ni4L6][1tBu]的分析，可以分离出由于与[NDI]•-笼的辅因子关联而产生的细微磁效应。这些发现建立了超分子笼作为对铁硫辅因子电子结构和氧化还原活性的第二球和外球效应进行反卷积的平台。
{"title":"Deconvoluting electrostatic, noncovalent, and magnetic effects of iron-sulfur cofactors inside synthetic cage frameworks.","authors":"Rupal Baliyan, Alejandro Javier Castillo, Brett N Schneider, Sudarshan Sharma, R Lee Penn, Gwendolyn A Bailey","doi":"10.1016/j.jinorgbio.2026.113292","DOIUrl":"https://doi.org/10.1016/j.jinorgbio.2026.113292","url":null,"abstract":"<p><p>The electronic states of iron‑sulfur (Fe-S) clusters in metalloenzymes are critically influenced by second and outer-sphere interactions-electrostatics, hydrogen bonding, and hydrophobic contacts-that modulate cofactor redox potentials and reactivity in processes ranging from cellular respiration to nitrogen fixation. To systematically probe these effects in a well-defined synthetic environment, we previously developed host-guest complexes of [Fe<sub>4</sub>S<sub>4</sub>(SR)<sub>4</sub>]<sup>2-</sup> clusters ([1<sup>R</sup>]<sup>2-</sup>, R = Ph, -CH<sub>2</sub>CH<sub>2</sub>OH) encapsulated within naphthalenediimide (NDI)-functionalized metal-organic cages [M<sub>4</sub>L<sub>6</sub>]<sup>8+</sup> (M = Fe, Ni, Zn; L = organic linker), demonstrating that encapsulation substantially alters cluster electronic structure. Herein, we quantitatively dissect the individual contributions from second and outer-sphere electrostatics, π-π stacking, hydrogen bonding, and magnetic coupling. By investigating the host-guest series in two charge states, 1<sup>R</sup>⊂[Ni<sub>4</sub>L<sub>6</sub>]<sup>6+</sup> and the reduced 1<sup>R</sup>⊂[Ni<sub>4</sub>L<sub>6</sub>]<sup>0</sup> framework featuring [NDI]<sup>•-</sup> radical panels, we isolate the specific influence of the host's electronic environment on the guest cofactors. As controls, we examine the free clusters and unencapsulated ion pairs [Ni<sub>4</sub>L<sub>6</sub>][1<sup>tBu</sup>]<sup>6+</sup> and [Ni<sub>4</sub>L<sub>6</sub>][1<sup>tBu</sup>], for which encapsulation is precluded by weak interfacial interactions and the smaller size of [1<sup>tBu</sup>]<sup>2-</sup>. In-depth Fe 2p X-ray photoelectron, infrared, and UV-visible spectroscopic analysis establishes substantial changes in binding energy and Fe-S bond covalency, with contributions from electrostatic stabilization (+0.6 eV binding energy shift) and second-sphere π-stacking/hydrogen bonding (+0.3 - 0.5 eV). Meanwhile, analysis of reduced congeners [Ni<sub>4</sub>L<sub>6</sub>]<sup>2+</sup>, 1<sup>R</sup>⊂[Ni<sub>4</sub>L<sub>6</sub>], and [Ni<sub>4</sub>L<sub>6</sub>][1<sup>tBu</sup>] enables dissection of subtle magnetic effects arising from cofactor association with the [NDI]<sup>•-</sup> cage. These findings establish supramolecular cages as a platform for deconvoluting second and outer-sphere effects on iron‑sulfur cofactor electronic structure and redox activity--.</p>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"280 ","pages":"113292"},"PeriodicalIF":3.2,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479354","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 : 2026-03-01Epub Date: 2025-11-24DOI: 10.1016/j.jinorgbio.2025.113155
Dariusz Wyrzykowski , Katarzyna Chmur , Jakub Brzeski , Artur Sikorski , Olga Tovchiga , Justyna Budka , Iwona Inkielewicz-Stępniak , Aleksandra Tesmar
This research aimed to compare the crystal structure, physicochemical, and biological properties of novel (acetylacetonate)(thiodiacetato)oxidovanadium(IV) complex salts, namely [QH][VO(acac)(tda)] (1) and [(acr)H][VO(acac)(tda)] (2) (acac = acetylacetonate, tda2− = thiodiacetate, Q = quinoline, acr = acridine) with previously reported oxydiacetate (oda−) analogues: [QH][VO(acac)(oda)] (3) and [(acr)H][VO(acac)(oda)](H2O)2 (4). A combination of experimental data, including X-ray crystallography, IR spectroscopy, potentiometric measurements and ESI-MS, and density functional theory (DFT) calculations enables thorough characterization of the complexes in the solid state and in solution. It has been demonstrated that the observed differences in the nature of VS (thioether) and VO (ether) dative bonds have only a slight impact on orbital energy levels and spin density distribution. At the same time, these minor differences do not significantly affect the thermodynamic stability of the complexes: logß1110 {[VO(acac)(tda)]−} = 16.91 and logß1110 {[VO(acac)(oda)]−} = 16.45. Additionally, the calculated thermodynamic parameters for the formation of these complexes (∆H, T∆S, ∆G in kcal mol−1, at 298 K) are −66.72, −16.38, and − 50.34 for [VO(acac)(tda)]−, and − 68.47, −15.64, and − 52.82 for [VO(acac)(oda)]−, respectively. The biological evaluations showed promising selective cytotoxic activity of the investigated complex salts against the human osteosarcoma cell line MG-63. The mechanism of biological action of these complexes appears to involve disruption of cell cycle regulation and induction of apoptosis. The counterions (acridine and quinoline) alone do not significantly affect cell cycle distribution, suggesting that the cytotoxic and cell cycle effects are primarily due to the [VO(acac)(tda)]− and [VO(acac)(oda)]− species.
{"title":"Thiodiacetate vs. oxydiacetate: physicochemical and biological properties of new heteroligand (acetylacetonate)oxidovanadium(IV) complexes","authors":"Dariusz Wyrzykowski , Katarzyna Chmur , Jakub Brzeski , Artur Sikorski , Olga Tovchiga , Justyna Budka , Iwona Inkielewicz-Stępniak , Aleksandra Tesmar","doi":"10.1016/j.jinorgbio.2025.113155","DOIUrl":"10.1016/j.jinorgbio.2025.113155","url":null,"abstract":"<div><div>This research aimed to compare the crystal structure, physicochemical, and biological properties of novel (acetylacetonate)(thiodiacetato)oxidovanadium(IV) complex salts, namely [QH][VO(acac)(tda)] (<strong>1</strong>) and [(acr)H][VO(acac)(tda)] (<strong>2</strong>) (acac = acetylacetonate, tda<sup>2−</sup> = thiodiacetate, Q = quinoline, acr = acridine) with previously reported oxydiacetate (oda<sup>−</sup>) analogues: [QH][VO(acac)(oda)] (<strong>3</strong>) and [(acr)H][VO(acac)(oda)](H<sub>2</sub>O)<sub>2</sub> (<strong>4</strong>). A combination of experimental data, including X-ray crystallography, IR spectroscopy, potentiometric measurements and ESI-MS, and density functional theory (DFT) calculations enables thorough characterization of the complexes in the solid state and in solution. It has been demonstrated that the observed differences in the nature of <em>V</em><img>S (thioether) and V<img>O (ether) dative bonds have only a slight impact on orbital energy levels and spin density distribution. At the same time, these minor differences do not significantly affect the thermodynamic stability of the complexes: log<em>ß</em><sub>1110</sub> {[VO(acac)(tda)]<sup>−</sup>} = 16.91 and log<em>ß</em><sub>1110</sub> {[VO(acac)(oda)]<sup>−</sup>} = 16.45. Additionally, the calculated thermodynamic parameters for the formation of these complexes (∆<em>H</em>, T∆<em>S</em>, ∆<em>G</em> in kcal mol<sup>−1</sup>, at 298 K) are −66.72, −16.38, and − 50.34 for [VO(acac)(tda)]<sup>−</sup>, and − 68.47, −15.64, and − 52.82 for [VO(acac)(oda)]<sup>−</sup>, respectively. The biological evaluations showed promising selective cytotoxic activity of the investigated complex salts against the human osteosarcoma cell line MG-63. The mechanism of biological action of these complexes appears to involve disruption of cell cycle regulation and induction of apoptosis. The counterions (acridine and quinoline) alone do not significantly affect cell cycle distribution, suggesting that the cytotoxic and cell cycle effects are primarily due to the [VO(acac)(tda)]<sup>−</sup> and [VO(acac)(oda)]<sup>−</sup> species.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"276 ","pages":"Article 113155"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600641","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 : 2026-03-01Epub Date: 2025-12-05DOI: 10.1016/j.jinorgbio.2025.113175
Keith Tang , Henry Tieu , Hanlin Liu , Naixin Zhao , Xiao-An Zhang
Metal-ligand stability plays a central role in medicinal bioinorganic chemistry, as it impacts not only the efficacy but also the safety profiles of metal-based therapeutic and diagnostic agents. Gadolinium-based contrast agents (GBCAs) have been widely applied in clinical magnetic resonance imaging (MRI) scans for decades to enhance the detection of otherwise hardly visible diseases. However, evidence of metal dissociation from Gd chelates in vivo have raised safety concerns and led to the withdrawals of several clinically approved GBCAs in recent years. Here we report an exceptionally high stability of Mn(III)tetracarboxylporphyrin (MnTCP), a Gd-free extracellular fluid CA with high MRI contrast enhancement efficiency at clinic magnetic fields. The stability of MnTCP was systematically investigated under challenging conditions known to cause metal dissociation or transmetallation of GBCAs, as well as most other chelated metal complexes. The kinetic inertness of MnTCP was demonstrated at low pH and high temperature, and no sign of metal dissociation was observed. Incubation of MnTCP with excess of various endogenous metal ions, as well as metal chelators also did not cause any observable transmetalation under neutral or acidic conditions up to 50 days. Moreover, MnTCP is highly stable against reduction by endogenous species, preventing the formation of labile Mn(II)-complex. These findings are consistent with in vivo and intracellular behaviors of MnTCP observed in previous studies. The abnormally high stability of this tetradentate coordination complex can be attributed to structural rigidity, aromaticity and strong metal-ligand orbital interactions.
{"title":"Exceptional stability of a Gd-free extracellular fluid MRI contrast agent based on manganese porphyrin","authors":"Keith Tang , Henry Tieu , Hanlin Liu , Naixin Zhao , Xiao-An Zhang","doi":"10.1016/j.jinorgbio.2025.113175","DOIUrl":"10.1016/j.jinorgbio.2025.113175","url":null,"abstract":"<div><div>Metal-ligand stability plays a central role in medicinal bioinorganic chemistry, as it impacts not only the efficacy but also the safety profiles of metal-based therapeutic and diagnostic agents. Gadolinium-based contrast agents (GBCAs) have been widely applied in clinical magnetic resonance imaging (MRI) scans for decades to enhance the detection of otherwise hardly visible diseases. However, evidence of metal dissociation from Gd chelates <em>in vivo</em> have raised safety concerns and led to the withdrawals of several clinically approved GBCAs in recent years. Here we report an exceptionally high stability of Mn(III)tetracarboxylporphyrin (MnTCP), a Gd-free extracellular fluid CA with high MRI contrast enhancement efficiency at clinic magnetic fields. The stability of MnTCP was systematically investigated under challenging conditions known to cause metal dissociation or transmetallation of GBCAs, as well as most other chelated metal complexes. The kinetic inertness of MnTCP was demonstrated at low pH and high temperature, and no sign of metal dissociation was observed. Incubation of MnTCP with excess of various endogenous metal ions, as well as metal chelators also did not cause any observable transmetalation under neutral or acidic conditions up to 50 days. Moreover, MnTCP is highly stable against reduction by endogenous species, preventing the formation of labile Mn(II)-complex. These findings are consistent with <em>in vivo</em> and intracellular behaviors of MnTCP observed in previous studies. The abnormally high stability of this tetradentate coordination complex can be attributed to structural rigidity, aromaticity and strong metal-ligand orbital interactions.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"276 ","pages":"Article 113175"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733865","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 : 2026-03-01Epub Date: 2025-12-06DOI: 10.1016/j.jinorgbio.2025.113180
Raúl Ramos , Ana María Plutín , Raúl Oscar Mocelo , Jean-Pierre DJukic , Camila Batista Pinto , Eduardo E. Castellano , Gustavo A. Echeverría , Oscar E. Piro , Mauricio F. Erben , Legna Colina-Vegas , Beatriz N. Cunha , Alzir A. Batista
In this work, we report the synthesis and characterization of three novel ruthenium(II) p-cymene complexes coordinated with acylthiourea ligands (L1−L3), of general formula [Ru(η6-p-cymene)(PPh3)(L1–L3)Cl]PF6 (1–3). Single-crystal X-ray crystallography of the free ligands and their complexes [Ru(η6-p-cymene)(PPh3) (κ1-S)-(N-benzoyl-N´-cyclopropylthiourea)Cl]PF6 (1), Ru(η6-p-cymene)(PPh3) (κ1-S)-(N-2-furoyl-N´-cyclopropylthiourea)Cl]PF6 (2), [Ru(η6-p-cymene)(PPh3)] (κ1-S)-(N-thiophene-2-carbonyl-N´-cyclopropyl thiourea)Cl]PF6 (3) revealed that the acylthiourea ligands act as neutral monodentate donors, coordinating through the sulfur atom (κ1-S). Application of the Extended Transition State–Natural Orbitals for Chemical Valence method demonstrated that the dominant interaction in complexes 1–3 originates from the overlap between the sulfur lone pair of the ligands and a Ru d-orbital, which plays a decisive role in their stability. The Interacting Quantum Atom analysis showed that both the free and coordinated acylthiourea ligands stabilize their structure through an intramolecular N–H···O=C hydrogen bond. The cytotoxicity of complexes 1–3 was evaluated against the A549 (lung) and MDA-MB-231 (breast) human cancer cell lines. To assess their selectivity, the compounds were also tested against two non-cancerous cell models: MRC-5 (lung fibroblasts) and MCF-10 A (breast epithelial cells). The study revealed high cytotoxicity against the MDA-MB-231 cell line, with IC₅₀ values of 0.62 ± 0.05 μM (1), 0.66 ± 0.12 μM (2), and 0.53 ± 0.12 μM (3). Activity against the A549 cell line was also significant, with IC₅₀ values of 1.05 ± 0.11 μM (1), 2.60 ± 0.25 μM (2), and 1.04 ± 0.21 μM (3). The combination of phosphine and acylthiourea ligands appears critical for achieving high cytotoxic activity.
{"title":"Synthesis, characterization, and anticancer activity of acylthiourea-ruthenium(II) p-cymene complexes","authors":"Raúl Ramos , Ana María Plutín , Raúl Oscar Mocelo , Jean-Pierre DJukic , Camila Batista Pinto , Eduardo E. Castellano , Gustavo A. Echeverría , Oscar E. Piro , Mauricio F. Erben , Legna Colina-Vegas , Beatriz N. Cunha , Alzir A. Batista","doi":"10.1016/j.jinorgbio.2025.113180","DOIUrl":"10.1016/j.jinorgbio.2025.113180","url":null,"abstract":"<div><div>In this work, we report the synthesis and characterization of three novel ruthenium(II) <em>p</em>-cymene complexes coordinated with acylthiourea ligands (<strong>L1−L3</strong>), of general formula [Ru(η<sup>6</sup>-<em>p</em>-cymene)(PPh<sub>3</sub>)(<strong>L1–L3</strong>)Cl]PF<sub>6</sub> (<strong>1–3</strong>). Single-crystal X-ray crystallography of the free ligands and their complexes [Ru(η<sup>6</sup>-<em>p</em>-cymene)(PPh<sub>3</sub>) (κ<sup>1</sup>-S)-(<em>N</em>-benzoyl-<em>N</em>´-cyclopropylthiourea)Cl]PF<sub>6</sub> (<strong>1</strong>), Ru(η<sup>6</sup>-<em>p</em>-cymene)(PPh<sub>3</sub>) (κ<sup>1</sup>-S)<em>-(N</em>-2-furoyl-<em>N</em>´-cyclopropylthiourea)Cl]PF<sub>6</sub> (<strong>2</strong>), [Ru(η<sup>6</sup>-<em>p</em>-cymene)(PPh<sub>3</sub>)] (κ<sup>1</sup>-S)-(<em>N</em>-thiophene-2-carbonyl-<em>N</em>´-cyclopropyl thiourea)Cl]PF<sub>6</sub> (<strong>3</strong>) revealed that the acylthiourea ligands act as neutral monodentate donors, coordinating through the sulfur atom (κ<sup>1</sup>-S). Application of the Extended Transition State–Natural Orbitals for Chemical Valence method demonstrated that the dominant interaction in complexes <strong>1–3</strong> originates from the overlap between the sulfur lone pair of the ligands and a Ru <em>d</em>-orbital, which plays a decisive role in their stability. The Interacting Quantum Atom analysis showed that both the free and coordinated acylthiourea ligands stabilize their structure through an intramolecular N–H···O=C hydrogen bond. The cytotoxicity of complexes <strong>1–3</strong> was evaluated against the A549 (lung) and MDA-MB-231 (breast) human cancer cell lines. To assess their selectivity, the compounds were also tested against two non-cancerous cell models: MRC-5 (lung fibroblasts) and MCF-10 A (breast epithelial cells). The study revealed high cytotoxicity against the MDA-MB-231 cell line, with IC₅₀ values of 0.62 ± 0.05 μM (<strong>1</strong>), 0.66 ± 0.12 μM (<strong>2</strong>), and 0.53 ± 0.12 μM (<strong>3</strong>). Activity against the A549 cell line was also significant, with IC₅₀ values of 1.05 ± 0.11 μM (<strong>1</strong>), 2.60 ± 0.25 μM (<strong>2</strong>), and 1.04 ± 0.21 μM (<strong>3</strong>). The combination of phosphine and acylthiourea ligands appears critical for achieving high cytotoxic activity.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"276 ","pages":"Article 113180"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712838","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 : 2026-03-01Epub Date: 2025-12-09DOI: 10.1016/j.jinorgbio.2025.113182
Dong-Woo Shin , Fangfang Zhong, Ekaterina V. Pletneva
The heme in the protein cytochrome (cyt) c is surrounded by loops C and D that differ in their sequences across species. Mutations G41S and Y48H in human (hu) cyt c are associated with thrombocytopenia and have been extensively studied. Herein, we describe effects of the same mutations in horse heart (hh) cyt c and make comparisons to those in the hu protein. While wild-type (WT) hu and hh cyt c proteins have similar global stabilities, unfolding of the hh protein is less cooperative. The differences are further amplified in the mutants. Loop dynamics were probed computationally through MD simulations and experimentally by characterizing the alkaline transition. With G41S and Y48H mutations in hh cyt c, loop C made fewer contacts with loop D and the dynamics of loop D were enhanced. Only the Y48H mutation decreased the reduction potential in hh cyt c, but both G41S and Y48H mutations increased the intrinsic peroxidase activity. The rate constant kf for the Met-to-Lys ligand switch in the alkaline transition differed in the hu and hh cyt c mutational series: this rate constant decreased upon mutations in the hu protein but increased with analogous mutations in the hh protein. The observed trends are rationalized based on the sequence variation in the two proteins, particularly the identity of residue 46 and differences in interactions it makes with loop D. Functional implications of the sequence difference for electron transfer and peroxidase activity are discussed.
{"title":"Differences in functional cross-talk between loops C and D in two mitochondrial cytochromes","authors":"Dong-Woo Shin , Fangfang Zhong, Ekaterina V. Pletneva","doi":"10.1016/j.jinorgbio.2025.113182","DOIUrl":"10.1016/j.jinorgbio.2025.113182","url":null,"abstract":"<div><div>The heme in the protein cytochrome (cyt) <em>c</em> is surrounded by loops C and D that differ in their sequences across species. Mutations G41S and Y48H in human (hu) cyt <em>c</em> are associated with thrombocytopenia and have been extensively studied. Herein, we describe effects of the same mutations in horse heart (hh) cyt <em>c</em> and make comparisons to those in the hu protein. While wild-type (WT) hu and hh cyt <em>c</em> proteins have similar global stabilities, unfolding of the hh protein is less cooperative. The differences are further amplified in the mutants. Loop dynamics were probed computationally through MD simulations and experimentally by characterizing the alkaline transition. With G41S and Y48H mutations in hh cyt <em>c</em>, loop C made fewer contacts with loop D and the dynamics of loop D were enhanced. Only the Y48H mutation decreased the reduction potential in hh cyt <em>c</em>, but both G41S and Y48H mutations increased the intrinsic peroxidase activity. The rate constant <em>k</em><sub>f</sub> for the Met-to-Lys ligand switch in the alkaline transition differed in the hu and hh cyt <em>c</em> mutational series: this rate constant decreased upon mutations in the hu protein but increased with analogous mutations in the hh protein. The observed trends are rationalized based on the sequence variation in the two proteins, particularly the identity of residue 46 and differences in interactions it makes with loop D. Functional implications of the sequence difference for electron transfer and peroxidase activity are discussed.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"276 ","pages":"Article 113182"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145779744","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 : 2026-03-01Epub Date: 2025-12-18DOI: 10.1016/j.jinorgbio.2025.113191
Andrew J. Smith , Cadmus D. Chen , Bochu Wang , Xiao Huang , Chenfengtao Zheng , Youhyun Nam , David N. Beratan
Charge transfer and transport are fundamental to chemistry and biochemistry. Since the 1950s, theorists and experimentalists have advanced the field to develop a molecular-level understanding of single-electron/one-step electron transfer, and ongoing studies explore multi-step, multi-electron, and multi-particle transfer and transport. This review highlights studies from our group on electron transfer beyond the one-electron/one-step regime. In particular, we review progress on electron bifurcation reactions, ultra-long range hopping transport in cable bacteria and bacterial nanowires, oxidative damage pathways, and charge transport pathways in nucleic acids. We highlight emerging themes and mechanisms across biological structures, including the roles being discovered for electron-electron correlations, rapid long-range multi-step biological electron transport, unconventional charge transport pathways, and competing charge transfer mechanisms.
{"title":"From single step hops to emergent biological phenomena","authors":"Andrew J. Smith , Cadmus D. Chen , Bochu Wang , Xiao Huang , Chenfengtao Zheng , Youhyun Nam , David N. Beratan","doi":"10.1016/j.jinorgbio.2025.113191","DOIUrl":"10.1016/j.jinorgbio.2025.113191","url":null,"abstract":"<div><div>Charge transfer and transport are fundamental to chemistry and biochemistry. Since the 1950s, theorists and experimentalists have advanced the field to develop a molecular-level understanding of single-electron/one-step electron transfer, and ongoing studies explore multi-step, multi-electron, and multi-particle transfer and transport. This review highlights studies from our group on electron transfer beyond the one-electron/one-step regime. In particular, we review progress on electron bifurcation reactions, ultra-long range hopping transport in cable bacteria and bacterial nanowires, oxidative damage pathways, and charge transport pathways in nucleic acids. We highlight emerging themes and mechanisms across biological structures, including the roles being discovered for electron-electron correlations, rapid long-range multi-step biological electron transport, unconventional charge transport pathways, and competing charge transfer mechanisms.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"276 ","pages":"Article 113191"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786844","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 : 2026-03-01Epub Date: 2025-12-05DOI: 10.1016/j.jinorgbio.2025.113179
Bruna V. Paes , Davi N. Costa , Igor V. Esarev , Susanne Boschuk , Petra Lippmann , Sarah Sant'Anna Maranhão , Claudia Pessoa , Ingo Ott , Heloisa Beraldo
The cyclometalated [Ir(CN)2(H2Ac4oClPh)]Cl·2H2O complex, hereafter named Ir(III) complex, was obtained from the reaction of dichlorotetrakis(2-(2-pyridinyl)phenyl)diiridium(III), [Ir2(NC)4Cl2] (P1) with 2-acetylpyridine N(4)-ortho-chlorophenyl thiosemicarbazone (H2Ac4oClPh). The Ir(III) complex and H2Ac4oClPh exhibited cytotoxic effects against A549 lung and PC3 prostate cancer cells, with IC50 values below 5 μM. Although the Ir(III) complex showed a higher IC50 value against PC3 prostate cancer cells than H2Ac4oClPh, it exhibited a higher selectivity index (SI = IC50 L929/IC50 PC3 L929: non-malignant fibroblast cells). The Ir(III) complex did not strongly inhibit thioredoxin reductase (TrxR) activity, suggesting that its mode of action does not involve TrxR inhibition. Hoechst 33342 staining revealed that A549 cells treated with the Ir(III) complex underwent nuclear fragmentation and chromatin condensation, indicating the occurrence of cell death. After 6 h treatment with Ir(III) complex, the iridium levels in A549 tumor cells were almost 75-fold higher than after treatment with the synthesis precursor P1, which probably could explain the potent cytotoxic effects of Ir(III) complex and the low activity of P1. The antibacterial activity of Ir(III) complex against Gram-positive Bacillus subtillis bacteria was comparable to that of ciprofloxacin used as a control. The results of the present work represent a significant contribution to the investigations on the pharmacological profile of iridium(III) complexes.
{"title":"A cyclometalated iridium(III) complex with 2-acetylpyridine-N(4)-ortho-chlorophenyl thiosemicarbazone: Potent antiproliferative and antibacterial activities","authors":"Bruna V. Paes , Davi N. Costa , Igor V. Esarev , Susanne Boschuk , Petra Lippmann , Sarah Sant'Anna Maranhão , Claudia Pessoa , Ingo Ott , Heloisa Beraldo","doi":"10.1016/j.jinorgbio.2025.113179","DOIUrl":"10.1016/j.jinorgbio.2025.113179","url":null,"abstract":"<div><div>The cyclometalated [Ir(C<img>N)<sub>2</sub>(H2Ac4<em>o</em>ClPh)]Cl·2H<sub>2</sub>O complex, hereafter named <strong>Ir(III) complex</strong>, was obtained from the reaction of dichlorotetrakis(2-(2-pyridinyl)phenyl)diiridium(III), [Ir<sub>2</sub>(N<img>C)<sub>4</sub>Cl<sub>2</sub>] (<strong>P1</strong>) with 2-acetylpyridine <em>N</em>(4)-ortho-chlorophenyl thiosemicarbazone (H2Ac4<em>o</em>ClPh). The <strong>Ir(III) complex</strong> and H2Ac4<em>o</em>ClPh exhibited cytotoxic effects against A549 lung and PC3 prostate cancer cells, with IC<sub>50</sub> values below 5 μM. Although the <strong>Ir(III) complex</strong> showed a higher IC<sub>50</sub> value against PC3 prostate cancer cells than H2Ac4<em>o</em>ClPh, it exhibited a higher selectivity index (SI = IC<sub>50 L929</sub>/IC<sub>50 PC3</sub> L929: non-malignant fibroblast cells). The <strong>Ir(III) complex</strong> did not strongly inhibit thioredoxin reductase (TrxR) activity, suggesting that its mode of action does not involve TrxR inhibition. Hoechst 33342 staining revealed that A549 cells treated with the <strong>Ir(III) complex</strong> underwent nuclear fragmentation and chromatin condensation, indicating the occurrence of cell death. After 6 h treatment with <strong>Ir(III) complex</strong>, the iridium levels in A549 tumor cells were almost 75-fold higher than after treatment with the synthesis precursor <strong>P1</strong>, which probably could explain the potent cytotoxic effects of <strong>Ir(III) complex</strong> and the low activity of <strong>P1</strong>. The antibacterial activity of <strong>Ir(III) complex</strong> against <em>Gram</em>-positive <em>Bacillus subtillis</em> bacteria was comparable to that of ciprofloxacin used as a control. The results of the present work represent a significant contribution to the investigations on the pharmacological profile of iridium(III) complexes.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"276 ","pages":"Article 113179"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733823","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 : 2026-03-01Epub Date: 2025-12-08DOI: 10.1016/j.jinorgbio.2025.113178
Emilia R. Serrano , Pedro M. David Gara , Juan J. Martínez Medina , Filippo Prencipe , Oscar E. Piro , Gustavo A. Echeverría , Gabriela Petroselli , Tatiana Da Ros , Gustavo T. Ruiz
A new complex fac-[(ferroceneCO2)ReI(CO)3(dppz)] (dppz = dipyrido[3,2-a:2′,3′-c]phenazine) was obtained and fully characterized by elemental analysis, 1H and 13C NMR, ESI-mass, IR and UV–vis spectroscopy. We also report new insights into the structural and photophysical properties of the fac-[(ferroceneCO2)ReI(CO)3L], where L = 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen), parent complexes. For all complexes, our results showed that: (i) no singlet oxygen generation was detected in acetonitrile solutions and (ii) they exhibited a very low luminescence quantum yield. However, photoacoustic measurements showed that under photoexcitation the complexes released all the absorbed energy to the medium as prompt heat. The antimicrobial activity of the ferroceneCO2-Re(CO)3(phen) complex was detected against both bacteria from American Type Culture Collections (ATCC) and clinically isolated bacterial strains. Antibacterial activity was rationalized in relation to extension of the π-system of the diamine ligands. Additionally, the ferroceneCO2-Re(CO)3(phen) complex showed no mutagenic potential.
合成了一种新的配合物-[（二茂铁eco2）ReI(CO)3(dppz)] （dppz =二吡啶[3,2- A:2′，3′-c]吩那嗪），并通过元素分析、1H和13C NMR、ESI-mass、IR和UV-vis光谱对其进行了表征。我们还报道了表面-[（二茂铁eco2）ReI(CO)3L]的结构和光物理性质的新见解，其中L = 2,2 ' -联吡啶（bpy）或1,10-菲罗啉（phen），母体配合物。对于所有配合物，我们的结果表明：(i)在乙腈溶液中没有检测到单线态氧生成，（ii）它们表现出非常低的发光量子产率。然而，光声测量表明，在光激发下，配合物将吸收的能量全部以提示热的形式释放到介质中。二茂铁eco2 - re (CO)3（phen）配合物对美国型培养菌（ATCC）和临床分离菌株的抑菌活性进行了检测。抗菌活性与二胺配体π体系的延伸有关。此外，二茂铁eco2 - re (CO)3（phen）配合物无致突变性。
{"title":"On the structural, photophysical and antimicrobial properties of bimetallic Re-Fe coordination compounds bearing diimines ligands","authors":"Emilia R. Serrano , Pedro M. David Gara , Juan J. Martínez Medina , Filippo Prencipe , Oscar E. Piro , Gustavo A. Echeverría , Gabriela Petroselli , Tatiana Da Ros , Gustavo T. Ruiz","doi":"10.1016/j.jinorgbio.2025.113178","DOIUrl":"10.1016/j.jinorgbio.2025.113178","url":null,"abstract":"<div><div>A new complex <em>fac</em>-[(ferroceneCO<sub>2</sub>)Re<sup>I</sup>(CO)<sub>3</sub>(dppz)] (dppz = dipyrido[3,2-a:2′,3′-c]phenazine) was obtained and fully characterized by elemental analysis, <sup>1</sup>H and <sup>13</sup>C NMR, ESI-mass, IR and UV–vis spectroscopy. We also report new insights into the structural and photophysical properties of the <em>fac</em>-[(ferroceneCO<sub>2</sub>)Re<sup>I</sup>(CO)<sub>3</sub>L], where L = 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen), parent complexes. For all complexes, our results showed that: (i) no singlet oxygen generation was detected in acetonitrile solutions and (ii) they exhibited a very low luminescence quantum yield. However, photoacoustic measurements showed that under photoexcitation the complexes released all the absorbed energy to the medium as prompt heat. The antimicrobial activity of the ferroceneCO<sub>2</sub>-Re(CO)<sub>3</sub>(phen) complex was detected against both bacteria from American Type Culture Collections (ATCC) and clinically isolated bacterial strains. Antibacterial activity was rationalized in relation to extension of the π-system of the diamine ligands. Additionally, the ferroceneCO<sub>2</sub>-Re(CO)<sub>3</sub>(phen) complex showed no mutagenic potential.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"276 ","pages":"Article 113178"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733863","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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