Sebastian B. Beil, Sylvestre Bonnet, Carla Casadevall, R. Detz, Fabian Eisenreich, Starla D. Glover, Christoph Kerzig, Line Næsborg, Sonja Pullen, Golo Storch, Ning Wei, Cathleen Zeymer
{"title":"Challenges and Future Perspectives in Photocatalysis: Conclusions from an Interdisciplinary Workshop","authors":"Sebastian B. Beil, Sylvestre Bonnet, Carla Casadevall, R. Detz, Fabian Eisenreich, Starla D. Glover, Christoph Kerzig, Line Næsborg, Sonja Pullen, Golo Storch, Ning Wei, Cathleen Zeymer","doi":"10.1021/jacsau.4c00527","DOIUrl":"https://doi.org/10.1021/jacsau.4c00527","url":null,"abstract":"","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":"23 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Iván Cheng-Sánchez, Katherine A. Gosselé, Leonardo Palaferri, E. Laul, Gionata Riccabella, R. K. Bedi, Yaozong Li, Anna Müller, Ivan Corbeski, A. Caflisch, Cristina Nevado
{"title":"Structure-Based Design of CBP/EP300 Degraders: When Cooperativity Overcomes Affinity","authors":"Iván Cheng-Sánchez, Katherine A. Gosselé, Leonardo Palaferri, E. Laul, Gionata Riccabella, R. K. Bedi, Yaozong Li, Anna Müller, Ivan Corbeski, A. Caflisch, Cristina Nevado","doi":"10.1021/jacsau.4c00292","DOIUrl":"https://doi.org/10.1021/jacsau.4c00292","url":null,"abstract":"","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":"76 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lei Guo, Meek Yang, Bin Dong, Seth Lewman, Alex Van Horn, Shang Jia
As a major family of red-shifted fluorophores that operate beyond visible light, polymethine dyes are pivotal in light-based biological techniques. However, methods for tuning this kind of fluorophores by structural modification remain restricted to bottom-up synthesis and modification using coupling or nucleophilic substitutions. In this study, we introduce a two-step, late-stage functionalization process for heptamethine dyes. This process enables the substitution of the central chlorine atom in the commonly used 4′-chloro heptamethine scaffold with various aryl groups using aryllithium reagents. This method borrows the building block and designs from the xanthene dye community and offers a mild and convenient way for the diversification of heptamethine fluorophores. Notably, this efficient conversion allows for the synthesis of heptamethine-X, the heptamethine scaffold with two ortho-substituents on the 4′-aryl modification, which brings enhanced stability and reduced aggregation to the fluorophore. We showcase the utility of this method by a facile synthesis of a fluorogenic, membrane-localizing fluorophore that outperforms its commercial counterparts with a significantly higher brightness and contrast. Overall, this method establishes the synthetic similarities between polymethine and xanthene fluorophores and provides a versatile and feasible toolbox for future optimizing heptamethine fluorophores for their biological applications.
{"title":"Engineering Central Substitutions in Heptamethine Dyes for Improved Fluorophore Performance","authors":"Lei Guo, Meek Yang, Bin Dong, Seth Lewman, Alex Van Horn, Shang Jia","doi":"10.1021/jacsau.4c00343","DOIUrl":"https://doi.org/10.1021/jacsau.4c00343","url":null,"abstract":"As a major family of red-shifted fluorophores that operate beyond visible light, polymethine dyes are pivotal in light-based biological techniques. However, methods for tuning this kind of fluorophores by structural modification remain restricted to bottom-up synthesis and modification using coupling or nucleophilic substitutions. In this study, we introduce a two-step, late-stage functionalization process for heptamethine dyes. This process enables the substitution of the central chlorine atom in the commonly used 4′-chloro heptamethine scaffold with various aryl groups using aryllithium reagents. This method borrows the building block and designs from the xanthene dye community and offers a mild and convenient way for the diversification of heptamethine fluorophores. Notably, this efficient conversion allows for the synthesis of heptamethine-X, the heptamethine scaffold with two ortho-substituents on the 4′-aryl modification, which brings enhanced stability and reduced aggregation to the fluorophore. We showcase the utility of this method by a facile synthesis of a fluorogenic, membrane-localizing fluorophore that outperforms its commercial counterparts with a significantly higher brightness and contrast. Overall, this method establishes the synthetic similarities between polymethine and xanthene fluorophores and provides a versatile and feasible toolbox for future optimizing heptamethine fluorophores for their biological applications.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141946204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aqueous proton transfer reactions are fundamental in biology and chemistry, yet kinetics and mechanisms of strong base–weak acid reactions are not well understood. In this work, we present a temperature-dependent reaction kinetic study of the water-soluble photobase actinoquinol, in the presence and absence of succinimide, a weak acid reaction partner. We study the temperature dependence of the reaction and connect the observed dynamics to the reaction’s thermodynamics. We find that actinoquinol reacts in associated complexes with water/succinimide, creating an intermediate complex that can undergo either dissociation to create products, or reverse proton transfer within the complex to recreate the initial reactants. We find that the intermediates’ formation is energetically unfavorable with both reaction partners, which impacts the net reaction rates. We also find that the net reaction rate is additionally strongly influenced by the competition between the dissociation of the intermediates and their reverse reaction.
{"title":"Temperature Effects and Activation Barriers in Aqueous Proton-Uptake Reactions","authors":"Balázs Antalicz, Huib J. Bakker","doi":"10.1021/jacsau.4c00326","DOIUrl":"https://doi.org/10.1021/jacsau.4c00326","url":null,"abstract":"Aqueous proton transfer reactions are fundamental in biology and chemistry, yet kinetics and mechanisms of strong base–weak acid reactions are not well understood. In this work, we present a temperature-dependent reaction kinetic study of the water-soluble photobase actinoquinol, in the presence and absence of succinimide, a weak acid reaction partner. We study the temperature dependence of the reaction and connect the observed dynamics to the reaction’s thermodynamics. We find that actinoquinol reacts in associated complexes with water/succinimide, creating an intermediate complex that can undergo either dissociation to create products, or reverse proton transfer within the complex to recreate the initial reactants. We find that the intermediates’ formation is energetically unfavorable with both reaction partners, which impacts the net reaction rates. We also find that the net reaction rate is additionally strongly influenced by the competition between the dissociation of the intermediates and their reverse reaction.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shobhan Mondal, Benjamin Gunschera, Berit Olofsson
Herein, we disclose a convenient protocol for the α-diarylation of carbon nucleophiles to yield heavily functionalized quaternary products. Diaryliodonium salts are utilized to transfer both aryl groups under transition-metal-free conditions, which enables an atom-efficient and high-yielding method with broad functional group tolerance. The methodology is amenable to a wide variety of carbon nucleophiles and can be utilized in late-stage functionalization of complex arenes. Furthermore, it is compatible with a new class of zwitterionic iodonium reagents, which gives access to phenols with an ortho-quaternary center. The diarylated products bear an ortho-iodo substituent that can be utilized in further transformations, including the formation of novel, functionalized six-membered cyclic iodonium salts.
{"title":"Transition-Metal-Free C-Diarylations to Reach All-Carbon Quaternary Centers","authors":"Shobhan Mondal, Benjamin Gunschera, Berit Olofsson","doi":"10.1021/jacsau.4c00500","DOIUrl":"https://doi.org/10.1021/jacsau.4c00500","url":null,"abstract":"Herein, we disclose a convenient protocol for the α-diarylation of carbon nucleophiles to yield heavily functionalized quaternary products. Diaryliodonium salts are utilized to transfer both aryl groups under transition-metal-free conditions, which enables an atom-efficient and high-yielding method with broad functional group tolerance. The methodology is amenable to a wide variety of carbon nucleophiles and can be utilized in late-stage functionalization of complex arenes. Furthermore, it is compatible with a new class of zwitterionic iodonium reagents, which gives access to phenols with an <i>ortho</i>-quaternary center. The diarylated products bear an <i>ortho</i>-iodo substituent that can be utilized in further transformations, including the formation of novel, functionalized six-membered cyclic iodonium salts.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141946205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cristina Bilanin, Amravati S. Singh, Lluis Martínez-Belenguer, Antonio Leyva-Pérez
The direct synthesis of terminal alkynes from widely available terminal alkenes is an unmet challenge in organic synthesis. Here, we show that alkyl and aromatic terminal alkenes can be converted to the corresponding alkynes in a one-pot process consisting of a Ru-catalyzed dehydrogenative hydrosilylation, followed by an oxidative dehydrogenative reaction of the vinyl silane intermediate, enabled by the combination of PhIO with BF3. This formal alkene dehydrogenation reaction with commercially available reagents and under mild reaction conditions gives access to terminal alkynes in a simple manner, including acetylene.
{"title":"One-Pot Synthesis of Terminal Alkynes from Alkenes","authors":"Cristina Bilanin, Amravati S. Singh, Lluis Martínez-Belenguer, Antonio Leyva-Pérez","doi":"10.1021/jacsau.4c00599","DOIUrl":"https://doi.org/10.1021/jacsau.4c00599","url":null,"abstract":"The direct synthesis of terminal alkynes from widely available terminal alkenes is an unmet challenge in organic synthesis. Here, we show that alkyl and aromatic terminal alkenes can be converted to the corresponding alkynes in a one-pot process consisting of a Ru-catalyzed dehydrogenative hydrosilylation, followed by an oxidative dehydrogenative reaction of the vinyl silane intermediate, enabled by the combination of PhIO with BF<sub>3</sub>. This formal alkene dehydrogenation reaction with commercially available reagents and under mild reaction conditions gives access to terminal alkynes in a simple manner, including acetylene.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":"130 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141946206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clémence Maingueneau, Anne-Elodie Lafargue, Stéphane Guillouet, Fabien Fillesoye, Thanh T. Cao Pham, Bénédicte F. Jordan, Cécile Perrio
Hypoxia, characterized by nonphysiological levels of oxygen tension, is a key phenomenon common to the majority of malignant tumors with poor prognosis. Many efforts have been made to develop hypoxia imaging for diagnosis, staging, and monitoring of diseases, as well as for evaluating therapies. PET Imaging using 18F-fluoronitroimidazoles (i.e., [18F]FMISO as a lead radiotracer) has demonstrated potential for clinical investigations, but the poor contrast and prolonged acquisition times (>2.5 h) strongly limit its accuracy and routine developments. Here, we report an original [18F]fluoronitroimidazole bearing a sulfo group ([18F]FLUSONIM) that displays highly hydrophilic properties and rapid clearance, providing high-performance hypoxia specific PET imaging. We describe the synthesis and radiosynthesis of [18F]FLUSONIM, its in vivo preclinical evaluation by PET imaging in healthy rats and a rhabdomyosarcoma rat model, as well as its radiometabolization and histological studies. [18F]FLUSONIM was prepared in a single step by high yielding radiofluorination of a sultone precursor, highlighting the advantages of this new radiolabeling approach not yet explored for radiopharmaceutical development. PET imaging experiments were conducted by systematically comparing [18F]FLUSONIM to [18F]FMISO as a reference. The overall results unequivocally demonstrate that the developed radiopharmaceutical meets the criteria of an ideal candidate for hypoxia PET imaging─rapid and efficient radiosynthesis, total stability, exclusive urinary elimination, high specificity for hypoxic regions, unprecedented tumor/background ratios, short acquisition delays (<60 min), and promising potential for further preclinical and clinical applications.
缺氧的特征是非生理水平的氧张力，它是大多数预后不良的恶性肿瘤的一个共同特征。人们一直在努力开发用于诊断、分期、监测疾病以及评估疗法的缺氧成像技术。使用18F-氟硝基咪唑（即[18F]FMISO作为先导放射性示踪剂）的正电子发射计算机断层成像已在临床研究中显示出潜力，但对比度差和采集时间长（2.5小时）极大地限制了其准确性和常规发展。在此，我们报告了一种带有磺基的原创[18F]氟硝基咪唑（[18F]FLUSONIM），它具有高度亲水性和快速清除性，可提供高性能的缺氧特异性 PET 成像。我们介绍了[18F]FLUSONIM 的合成和放射合成、在健康大鼠和横纹肌肉瘤大鼠模型中通过 PET 成像对其进行的体内临床前评估，以及其放射代谢和组织学研究。[18F]FLUSONIM是通过对一种苏丹酮前体进行高产率放射性氟化一步制备而成的，突出了这种尚未用于放射性药物开发的新型放射性标记方法的优势。通过系统比较[18F]FLUSONIM 和作为参照物的[18F]FMISO，进行了 PET 成像实验。总体结果明确表明，所开发的放射性药物符合缺氧 PET 成像理想候选药物的标准--快速高效的放射合成、完全稳定、完全通过尿液排出、对缺氧区域具有高度特异性、前所未有的肿瘤/背景比、较短的采集延迟（60 分钟），以及进一步临床前和临床应用的巨大潜力。
{"title":"18F-Fluorination of Nitroimidazolyl-Containing Sultone: A Direct Access to a Highly Hydrophilic Radiotracer for High-Performance Positron Emission Tomography Imaging of Hypoxia","authors":"Clémence Maingueneau, Anne-Elodie Lafargue, Stéphane Guillouet, Fabien Fillesoye, Thanh T. Cao Pham, Bénédicte F. Jordan, Cécile Perrio","doi":"10.1021/jacsau.4c00546","DOIUrl":"https://doi.org/10.1021/jacsau.4c00546","url":null,"abstract":"Hypoxia, characterized by nonphysiological levels of oxygen tension, is a key phenomenon common to the majority of malignant tumors with poor prognosis. Many efforts have been made to develop hypoxia imaging for diagnosis, staging, and monitoring of diseases, as well as for evaluating therapies. PET Imaging using <sup>18</sup>F-fluoronitroimidazoles (i.e., [<sup>18</sup>F]FMISO as a lead radiotracer) has demonstrated potential for clinical investigations, but the poor contrast and prolonged acquisition times (>2.5 h) strongly limit its accuracy and routine developments. Here, we report an original [<sup>18</sup>F]fluoronitroimidazole bearing a sulfo group ([<sup>18</sup>F]FLUSONIM) that displays highly hydrophilic properties and rapid clearance, providing high-performance hypoxia specific PET imaging. We describe the synthesis and radiosynthesis of [<sup>18</sup>F]FLUSONIM, its <i>in vivo</i> preclinical evaluation by PET imaging in healthy rats and a rhabdomyosarcoma rat model, as well as its radiometabolization and histological studies. [<sup>18</sup>F]FLUSONIM was prepared in a single step by high yielding radiofluorination of a sultone precursor, highlighting the advantages of this new radiolabeling approach not yet explored for radiopharmaceutical development. PET imaging experiments were conducted by systematically comparing [<sup>18</sup>F]FLUSONIM to [<sup>18</sup>F]FMISO as a reference. The overall results unequivocally demonstrate that the developed radiopharmaceutical meets the criteria of an ideal candidate for hypoxia PET imaging─rapid and efficient radiosynthesis, total stability, exclusive urinary elimination, high specificity for hypoxic regions, unprecedented tumor/background ratios, short acquisition delays (<60 min), and promising potential for further preclinical and clinical applications.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141881701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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