Laia Saltor Núñez, Vajinder Kumar, James F. Ross, Jonathan P. Dolan, Sumitra Srimasorn, Xiaoli Zhang, Ralf P. Richter* and W. Bruce Turnbull*,
{"title":"","authors":"Laia Saltor Núñez, Vajinder Kumar, James F. Ross, Jonathan P. Dolan, Sumitra Srimasorn, Xiaoli Zhang, Ralf P. Richter* and W. Bruce Turnbull*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":8.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/jacsau.5c00305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144343238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2025-06-11DOI: 10.1021/jacsau.5c0021710.1021/jacsau.5c00217
Martin Schaier, Dina Baier, Sarah Theiner, Walter Berger* and Gunda Koellensperger*,
{"title":"LA-ICP-TOFMS Imaging Reveals Significant Influence of Cancer Cell Resistance on Oxaliplatin Compartmentalization in the Tumor Microenvironment","authors":"Martin Schaier, Dina Baier, Sarah Theiner, Walter Berger* and Gunda Koellensperger*, ","doi":"10.1021/jacsau.5c0021710.1021/jacsau.5c00217","DOIUrl":"https://doi.org/10.1021/jacsau.5c00217https://doi.org/10.1021/jacsau.5c00217","url":null,"abstract":"<p >Chemoresistance in cancer cells, particularly in refractory types, such as colorectal cancer, poses a major challenge to effective treatment. In particular, the interaction between cancer cells and the tumor microenvironment (TME) has been shown to exert substantial influence on the efficacy of therapeutic agents. This study investigated whether an intrinsic resistance phenotype alters drug distribution in the TME using xenograft models derived from HCT116 colorectal cancer cells, including oxaliplatin (OxPt)-sensitive and OxPt-resistant (OxR) variants. Tumors were prepared as formalin-fixed paraffin-embedded (FFPE) sections, followed by single-cell analysis with laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS). Based on histological evaluations, a panel of metal-conjugated antibodies was designed to target tissue architecture and distinct cell states within the TME. A dedicated calibration strategy was applied to accurately measure platinum (Pt) uptake in phenotypically defined single cells across both the tumor and its microenvironment. The results revealed substantial structural differences: HCT116/OxR tumors exhibited robust growth following drug administration, while parental tumors displayed extensive degradation. Notably, OxPt accumulated significantly in necrotic regions specific to HCT116/OxR, indicating resistance-dependent changes in drug compartmentalization. These findings suggest that an intrinsically resistant cancer cell phenotype is capable of markedly altering metal distributions within the TME.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 6","pages":"2619–2631 2619–2631"},"PeriodicalIF":8.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2025-06-11DOI: 10.1021/jacsau.5c0032010.1021/jacsau.5c00320
Hsien-Liang Cho, Daoyang Zhang and Alison R. Fout*,
{"title":"Nonheme Iron Catalyst Selectively Activates Oxygen to Hydrogen Peroxide","authors":"Hsien-Liang Cho, Daoyang Zhang and Alison R. Fout*, ","doi":"10.1021/jacsau.5c0032010.1021/jacsau.5c00320","DOIUrl":"https://doi.org/10.1021/jacsau.5c00320https://doi.org/10.1021/jacsau.5c00320","url":null,"abstract":"<p >Iron complexes are known for their excellent reactivity toward the oxygen reduction reaction (ORR), which proceeds via two possible pathways: a two-electron/two-proton (2e<sup>–</sup>/2H<sup>+</sup>) process to form hydrogen peroxide or a four-electron/four-proton (4e<sup>–</sup>/4H<sup>+</sup>) process to form water. Developing catalysts that enable selective oxygen reduction remains a challenge. Inspired by heme-based systems, we designed two iron complexes incorporating secondary coordination sphere interactions to investigate their influence on the ORR selectivity. The complexes, [Py<sub>2</sub>Py(afa<sup>Cy</sup>)<sub>2</sub>Fe]OTf<sub>2</sub> and [N(afa<sup>Cy</sup>)<sub>3</sub>Fe]OTf<sub>2</sub>, were evaluated for their catalytic activity using decamethylferrocene as the reductant, with reaction progress monitored via absorbance spectroscopy. [Py<sub>2</sub>Py(afa<sup>Cy</sup>)<sub>2</sub>Fe]OTf<sub>2</sub> exhibited a selectivity profile comparable to iron porphyrin but with a slower kinetic rate, likely due to the steric hindrance from ligand functionalization. [N(afa<sup>Cy</sup>)<sub>3</sub>Fe]OTf<sub>2</sub> demonstrated exceptional selectivity toward the 2e<sup>–</sup>/2H<sup>+</sup> pathway, a rare observation for nonheme iron complexes. Kinetic measurements revealed that the catalytic reaction with [N(afa<sup>Cy</sup>)<sub>3</sub>Fe]OTf<sub>2</sub> follows second-order kinetics with a rate constant of 81 mM<sup>–1</sup> s<sup>–1</sup>. We propose that the rate-determining step involves electron transfer from decamethylferrocene to the hydroperoxo iron(III) complex, occurring through a stepwise proton transfer/electron transfer (PTET) or electron transfer/proton transfer (ETPT) process, followed by hydrogen peroxide dissociation.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 6","pages":"2713–2719 2713–2719"},"PeriodicalIF":8.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00320","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2025-06-11DOI: 10.1021/jacsau.5c0043810.1021/jacsau.5c00438
Erika McCarthy, Dariya Baizhigitova, Jia-Min Chu and Yong Zhang*,
{"title":"Oxidative and Hydrolytic HNO Formation from a Clinical Drug Hydroxyurea Catalyzed by Horseradish Peroxidase: Basic Mechanism, Active Site Effect, and Implications for Drug Design","authors":"Erika McCarthy, Dariya Baizhigitova, Jia-Min Chu and Yong Zhang*, ","doi":"10.1021/jacsau.5c0043810.1021/jacsau.5c00438","DOIUrl":"https://doi.org/10.1021/jacsau.5c00438https://doi.org/10.1021/jacsau.5c00438","url":null,"abstract":"<p >HNO plays an important role in many biological processes related to vasodilation, regulation of enzyme activities, and neurological functions. The understanding of enzymatic oxidative HNO-releasing pathways in biology remains scarce. We investigated HNO formation from a well-established small-molecule drug hydroxyurea catalyzed by horseradish peroxidase (HRP). Density functional theory results reveal two sequential proton-coupled electron transfers from hydroxyurea to HRP Compound I as the most favorable mechanism for HNO generation, which was found to be kinetically feasible and thermodynamically favorable. This is consistent with its experimentally observed reactivity. Moreover, the large active site model study uncovered interesting conformation changes involving HRP’s amino acid H-bonding network through the reaction pathway, which were employed to anchor the evolving substrate via its key CONH<sub>2</sub> moiety. Detailed computational analysis reveals some useful structural properties for future drug development. In addition, this study presents the first computational investigation of the full reaction mechanism of acyl nitroso hydrolysis for HNO generation, supporting the experimentally observed facile reactivity. Overall, this study reveals, for the first time, the detailed computational reaction mechanism of enzymatic oxidative and hydrolytic HNO generation from a clinical drug, providing structural features beneficial for future drug design.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 6","pages":"2849–2860 2849–2860"},"PeriodicalIF":8.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00438","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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