Copper-mediated programmed cell death, which influences the regulation of tumor progression, is an effective approach for antitumor molecular therapy. Unlike apoptosis, copper complex-induced cuproptosis by lipid-acylated protein aggregation triggers the mitochondrial proteotoxic stress response, which could be associated with immunomodulation. However, it remains a great challenge to understand the distinctive molecular mechanisms that presumably activate immunity by cuproptosis. Here, the new nonlabeling fluorescent molecular tools of Cu-DPPZ-Py+ and Cu-DPPZ-Ph are synthesized and used to investigate the differential immune signaling mechanisms induced by copper-mediated cuproptosis or apoptosis. With Cu-DPPZ-Py+ and Cu-Elesclomol, there is strong evidence that the triggering cuproptosis significantly drives mitochondrial DNA (mtDNA) release to activate innate immunity via cyclic GMP-AMP synthase-stimulation of interferon genes (cGAS-STING), which can improve T cell antitumor immunity in vivo. By contrast, it is observed that Cu-DPPZ-Ph treated tumor cells could release intracellular caspase-3, resulting in apoptosis-associated immunosuppression. This study supports insights into how cuproptosis bridges cGAS-STING immune pathways, contributing to the development of cuproptosis-based antitumor immunotherapy.
{"title":"Signaling Mechanism of Cuproptosis Activating cGAS-STING Immune Pathway","authors":"Chengyuan Zhu, Jialiang Li, Wanying Sun, Desheng Li, Yiliang Wang, Xing-Can Shen","doi":"10.1021/jacsau.4c00712","DOIUrl":"https://doi.org/10.1021/jacsau.4c00712","url":null,"abstract":"Copper-mediated programmed cell death, which influences the regulation of tumor progression, is an effective approach for antitumor molecular therapy. Unlike apoptosis, copper complex-induced cuproptosis by lipid-acylated protein aggregation triggers the mitochondrial proteotoxic stress response, which could be associated with immunomodulation. However, it remains a great challenge to understand the distinctive molecular mechanisms that presumably activate immunity by cuproptosis. Here, the new nonlabeling fluorescent molecular tools of Cu-DPPZ-Py<sup>+</sup> and Cu-DPPZ-Ph are synthesized and used to investigate the differential immune signaling mechanisms induced by copper-mediated cuproptosis or apoptosis. With Cu-DPPZ-Py<sup>+</sup> and Cu-Elesclomol, there is strong evidence that the triggering cuproptosis significantly drives mitochondrial DNA (mtDNA) release to activate innate immunity via cyclic GMP-AMP synthase-stimulation of interferon genes (cGAS-STING), which can improve T cell antitumor immunity <i>in vivo</i>. By contrast, it is observed that Cu-DPPZ-Ph treated tumor cells could release intracellular caspase-3, resulting in apoptosis-associated immunosuppression. This study supports insights into how cuproptosis bridges cGAS-STING immune pathways, contributing to the development of cuproptosis-based antitumor immunotherapy.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267175","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}
Decoupled water electrolysis systems, incorporating a reversible redox mediator that allows for the construction of membrane-free electrolyzers, have emerged as a promising approach to produce high-purity hydrogen with remarkable flexibility. The key factor crucial for practical applications lies in the development of mediator electrodes that possess suitable redox potential, high redox capacity, excellent cycling reversibility and stability. Herein, we introduce a novel concept of oxygen-mediating redox mediators (ORMs) employing Bi2O3 as an example material, which are capable of sequestering oxygen during the hydrogen evolution reaction and subsequently releasing it to generate oxygen gas under alkaline conditions. Thanks to its remarkable reversible redox activity and specific capacity, the Bi2O3 electrode boasts an impressive reversible specific capacity of 300.8 mA h g–1 and delivers outstanding cycling performance for >1000 cycles at a current density of 2.0 A g–1. Furthermore, the implementation of such a decoupled alkaline water electrolysis system can be integrated with a Bi2O3–Zn battery, enabling both power-to-fuel (hydrogen production) and chemical-to-power (rechargeable Bi2O3–Zn battery) conversion. With many oxygen-carrier materials readily available and the potential integration with rechargeable alkaline batteries, this study provides an alternative competitive route for membrane-free decoupled water splitting through the oxygen-mediating mechanism with combined energy transformation and storage.
解耦水电解系统包含一种可逆氧化还原介质，可用于建造无膜电解器，是一种具有显著灵活性的生产高纯度氢气的可行方法。实际应用的关键因素在于开发具有合适氧化还原电位、高氧化还原容量、出色的循环可逆性和稳定性的介质电极。在此，我们以 Bi2O3 为例，介绍了氧介导氧化还原介质（ORMs）的新概念，这种介质能够在氢气进化反应过程中封存氧气，并在碱性条件下释放氧气以生成含氧气体。由于具有出色的可逆氧化还原活性和比容量，Bi2O3 电极的可逆比容量达到了令人印象深刻的 300.8 mA h g-1，并且在电流密度为 2.0 A g-1 的条件下可循环使用 1000 次，具有出色的循环性能。此外，这种解耦碱性水电解系统可与 Bi2O3-Zn 电池集成，实现电力到燃料（制氢）和化学到电力（可充电 Bi2O3-Zn 电池）的转换。由于许多载氧材料都很容易获得，而且有可能与可充电碱性电池集成，这项研究为通过氧介导机制进行无膜解耦水分裂提供了另一条具有竞争力的途径，同时还能实现能量转化和储存。
{"title":"Decoupling Electrolytic Water Splitting by an Oxygen-Mediating Process","authors":"Mingze Xu, Jianying Wang, Shi-Gang Sun, Zuofeng Chen","doi":"10.1021/jacsau.4c00710","DOIUrl":"https://doi.org/10.1021/jacsau.4c00710","url":null,"abstract":"Decoupled water electrolysis systems, incorporating a reversible redox mediator that allows for the construction of membrane-free electrolyzers, have emerged as a promising approach to produce high-purity hydrogen with remarkable flexibility. The key factor crucial for practical applications lies in the development of mediator electrodes that possess suitable redox potential, high redox capacity, excellent cycling reversibility and stability. Herein, we introduce a novel concept of oxygen-mediating redox mediators (ORMs) employing Bi<sub>2</sub>O<sub>3</sub> as an example material, which are capable of sequestering oxygen during the hydrogen evolution reaction and subsequently releasing it to generate oxygen gas under alkaline conditions. Thanks to its remarkable reversible redox activity and specific capacity, the Bi<sub>2</sub>O<sub>3</sub> electrode boasts an impressive reversible specific capacity of 300.8 mA h g<sup>–1</sup> and delivers outstanding cycling performance for >1000 cycles at a current density of 2.0 A g<sup>–1</sup>. Furthermore, the implementation of such a decoupled alkaline water electrolysis system can be integrated with a Bi<sub>2</sub>O<sub>3</sub>–Zn battery, enabling both power-to-fuel (hydrogen production) and chemical-to-power (rechargeable Bi<sub>2</sub>O<sub>3</sub>–Zn battery) conversion. With many oxygen-carrier materials readily available and the potential integration with rechargeable alkaline batteries, this study provides an alternative competitive route for membrane-free decoupled water splitting through the oxygen-mediating mechanism with combined energy transformation and storage.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267222","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}
Sakthi Raje, Subhash Garhwal, Katarzyna Młodzikowska-Pieńko, Tofayel Sheikh Mohammad, Ron Raphaeli, Natalia Fridman, Linda J. W. Shimon, Renana Gershoni-Poranne, Graham de Ruiter
With growing efforts pushing toward sustainable catalysis, using earth-abundant metals has become increasingly important. Here, we present the first examples of cobalt PCNHCP pincer complexes that demonstrate dual stereoselectivity for allyl ether isomerization. While the cationic cobalt complex [((PCNHCP)Co)2-μ-N2][BAr4F]2 (3) mainly favors the Z-isomer of the enol ether, the corresponding methyl complex [(PCNHCP)CoMe] (4) mostly gives the E-isomer. The dichotomy in selectivity was investigated computationally, revealing important contributions from the substituents on the metal (N2 vs Me), including a 1,2-alkyl migration from cobalt to the N-heterocyclic carbene (NHC) of the methyl substituent, which is further explored in this report.
{"title":"N2 Dissociation vs Reversible 1,2-Methyl Migration in PCNHCP Cobalt(I) Complexes in the Stereoselective Isomerization (E/Z) of Allyl Ethers","authors":"Sakthi Raje, Subhash Garhwal, Katarzyna Młodzikowska-Pieńko, Tofayel Sheikh Mohammad, Ron Raphaeli, Natalia Fridman, Linda J. W. Shimon, Renana Gershoni-Poranne, Graham de Ruiter","doi":"10.1021/jacsau.4c00529","DOIUrl":"https://doi.org/10.1021/jacsau.4c00529","url":null,"abstract":"With growing efforts pushing toward sustainable catalysis, using earth-abundant metals has become increasingly important. Here, we present the first examples of cobalt PC<sub>NHC</sub>P pincer complexes that demonstrate dual stereoselectivity for allyl ether isomerization. While the cationic cobalt complex [((PC<sub>NHC</sub>P)Co)<sub>2</sub>-μ-N<sub>2</sub>][BAr<sub>4</sub><sup>F</sup>]<sub>2</sub> (<b>3</b>) mainly favors the <i>Z</i>-isomer of the enol ether, the corresponding methyl complex [(PC<sub>NHC</sub>P)CoMe] (<b>4</b>) mostly gives the <i>E</i>-isomer. The dichotomy in selectivity was investigated computationally, revealing important contributions from the substituents on the metal (N<sub>2</sub> vs Me), including a 1,2-alkyl migration from cobalt to the N-heterocyclic carbene (NHC) of the methyl substituent, which is further explored in this report.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267221","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}
Liquid–liquid phase separation of biomolecules is increasingly recognized as being relevant to various cellular functions, and complex coacervation of biomacromolecules, particularly proteins, is emerging as a key mechanism for this phenomenon. Complex coacervation is also being explored as a potential protein purification method due to its potential scalability, aqueous operation, and ability to produce a highly concentrated product. However, to date, most studies of complex coacervation have evaluated the phase behavior of a binary mixture of two oppositely charged macromolecules. Therefore, a comprehensive understanding of the phase behavior of complex biological mixtures is yet to be established. To address this, a panel of engineered proteins was designed to allow for quantitative analysis of the complex coacervation of individual proteins within a multicomponent mixture. The behavior of individual proteins was evaluated using a defined mixture of proteins that mimics the charge profile of the Escherichia coli proteome. To allow for the direct quantification of proteins in each phase, spectrally separated fluorescent proteins were used to construct the protein mixture. From this quantitative analysis, we observed that protein coacervation was synchronized in the mixture, which was distinctive from the behavior when each protein was evaluated in a single-protein system. Subtle differences in biophysical properties between the proteins, such as the ionization of individual charged residues and overall charge density, became noticeable in the mixture, which allowed us to elucidate parameters for protein complex coacervation. With this understanding, we successfully designed methods to enrich a range of proteins of interest from a mixture of proteins.
{"title":"Selectivity of Complex Coacervation in Multiprotein Mixtures","authors":"So Yeon Ahn, Allie C. Obermeyer","doi":"10.1021/jacsau.4c00399","DOIUrl":"https://doi.org/10.1021/jacsau.4c00399","url":null,"abstract":"Liquid–liquid phase separation of biomolecules is increasingly recognized as being relevant to various cellular functions, and complex coacervation of biomacromolecules, particularly proteins, is emerging as a key mechanism for this phenomenon. Complex coacervation is also being explored as a potential protein purification method due to its potential scalability, aqueous operation, and ability to produce a highly concentrated product. However, to date, most studies of complex coacervation have evaluated the phase behavior of a binary mixture of two oppositely charged macromolecules. Therefore, a comprehensive understanding of the phase behavior of complex biological mixtures is yet to be established. To address this, a panel of engineered proteins was designed to allow for quantitative analysis of the complex coacervation of individual proteins within a multicomponent mixture. The behavior of individual proteins was evaluated using a defined mixture of proteins that mimics the charge profile of the <i>Escherichia coli</i> proteome. To allow for the direct quantification of proteins in each phase, spectrally separated fluorescent proteins were used to construct the protein mixture. From this quantitative analysis, we observed that protein coacervation was synchronized in the mixture, which was distinctive from the behavior when each protein was evaluated in a single-protein system. Subtle differences in biophysical properties between the proteins, such as the ionization of individual charged residues and overall charge density, became noticeable in the mixture, which allowed us to elucidate parameters for protein complex coacervation. With this understanding, we successfully designed methods to enrich a range of proteins of interest from a mixture of proteins.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267224","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}
Yuqin Qian, Zhi-Chao Huang-Fu, Hao Li, Tong Zhang, Xia Li, Sydney Schmidt, Haley Fisher, Jesse B. Brown, Avetik Harutyunyan, Hanning Chen, Gugang Chen, Yi Rao
Short-wave infrared (SWIR) imaging systems offer remarkable advantages, such as enhanced resolution and contrast, compared to their optical counterparts. However, broader applications demand improvements in performance, notably the elimination of cryogenic temperature requirements and cost reduction in manufacturing processes. In this manuscript, we present a new development in SWIR photodetection, exploiting the potential of metal halide perovskite materials. Our work introduces a cost-effective and easily fabricated SWIR photodetector with an ultrabroad detection range from 900 to 2500 nm, a room-temperature responsivity of 1.57 × 102 A/W, and a specific detectivity of 4.18 × 1010 Jones at 1310 nm. We then performed comprehensive static and time-resolved optical and electrical measurements under ambient conditions, complemented by extensive density functional theory simulations, validating the formation of heterojunctions within the intrinsic n-type and extrinsic p-type perovskite structures. The potential of our perovskite-based SWIR materials extends from photodetectors to photovoltaic cells and introduces a possibility for high SWIR responsivity at room temperature and atmospheric pressure, which promotes its economic efficiency.
{"title":"Unleashing the Potential: High Responsivity at Room Temperature of Halide Perovskite-Based Short-Wave Infrared Detectors with Ultrabroad Bandwidth","authors":"Yuqin Qian, Zhi-Chao Huang-Fu, Hao Li, Tong Zhang, Xia Li, Sydney Schmidt, Haley Fisher, Jesse B. Brown, Avetik Harutyunyan, Hanning Chen, Gugang Chen, Yi Rao","doi":"10.1021/jacsau.4c00621","DOIUrl":"https://doi.org/10.1021/jacsau.4c00621","url":null,"abstract":"Short-wave infrared (SWIR) imaging systems offer remarkable advantages, such as enhanced resolution and contrast, compared to their optical counterparts. However, broader applications demand improvements in performance, notably the elimination of cryogenic temperature requirements and cost reduction in manufacturing processes. In this manuscript, we present a new development in SWIR photodetection, exploiting the potential of metal halide perovskite materials. Our work introduces a cost-effective and easily fabricated SWIR photodetector with an ultrabroad detection range from 900 to 2500 nm, a room-temperature responsivity of 1.57 × 10<sup>2</sup> A/W, and a specific detectivity of 4.18 × 10<sup>10</sup> Jones at 1310 nm. We then performed comprehensive static and time-resolved optical and electrical measurements under ambient conditions, complemented by extensive density functional theory simulations, validating the formation of heterojunctions within the intrinsic <i>n</i>-type and extrinsic <i>p</i>-type perovskite structures. The potential of our perovskite-based SWIR materials extends from photodetectors to photovoltaic cells and introduces a possibility for high SWIR responsivity at room temperature and atmospheric pressure, which promotes its economic efficiency.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267225","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}
Hahyoun Park, Cham Bi Seo, Jaesook Yun, Hyunwoo Kim
This study aims to develop a method for the chiral analysis of organoboron compounds using nuclear magnetic resonance (NMR) spectroscopy. It addresses the longstanding challenge associated with these chiral organoboron compounds, which often require derivatization and pretreatment prior to chromatographic analysis. Our method utilizes tridentate ligands to facilitate effective ligand exchange and incorporates fluorine labels, allowing for the precise discrimination of 19F NMR signals. This is achieved in conjunction with a chiral cationic cobalt complex, serving as the chiral solvating agent. This approach provides reliable and rapid determination of enantiomeric excess in a wide range of organoboron compounds, featuring various functional groups, and establishes a universal tool for assessing the optical purity of these substances.
{"title":"19F NMR-Based Chiral Analysis of Organoboron Compounds via Chiral Recognition of Fluorine-Labeled Boronates with Cobalt Complexes","authors":"Hahyoun Park, Cham Bi Seo, Jaesook Yun, Hyunwoo Kim","doi":"10.1021/jacsau.4c00703","DOIUrl":"https://doi.org/10.1021/jacsau.4c00703","url":null,"abstract":"This study aims to develop a method for the chiral analysis of organoboron compounds using nuclear magnetic resonance (NMR) spectroscopy. It addresses the longstanding challenge associated with these chiral organoboron compounds, which often require derivatization and pretreatment prior to chromatographic analysis. Our method utilizes tridentate ligands to facilitate effective ligand exchange and incorporates fluorine labels, allowing for the precise discrimination of <sup>19</sup>F NMR signals. This is achieved in conjunction with a chiral cationic cobalt complex, serving as the chiral solvating agent. This approach provides reliable and rapid determination of enantiomeric excess in a wide range of organoboron compounds, featuring various functional groups, and establishes a universal tool for assessing the optical purity of these substances.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267223","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}
Junkil Park, Honghui Kim, Yeonghun Kang, Yunsung Lim, Jihan Kim
Renowned for their high porosity and structural diversity, metal–organic frameworks (MOFs) are a promising class of materials for a wide range of applications. In recent decades, with the development of large-scale databases, the MOF community has witnessed innovations brought by data-driven machine learning methods, which have enabled a deeper understanding of the chemical nature of MOFs and led to the development of novel structures. Notably, machine learning is continuously and rapidly advancing as new methodologies, architectures, and data representations are actively being investigated, and their implementation in materials discovery is vigorously pursued. Under these circumstances, it is important to closely monitor recent research trends and identify the technologies that are being introduced. In this Perspective, we focus on emerging trends of machine learning within the field of MOFs, the challenges they face, and the future directions of their development.
{"title":"From Data to Discovery: Recent Trends of Machine Learning in Metal–Organic Frameworks","authors":"Junkil Park, Honghui Kim, Yeonghun Kang, Yunsung Lim, Jihan Kim","doi":"10.1021/jacsau.4c00618","DOIUrl":"https://doi.org/10.1021/jacsau.4c00618","url":null,"abstract":"Renowned for their high porosity and structural diversity, metal–organic frameworks (MOFs) are a promising class of materials for a wide range of applications. In recent decades, with the development of large-scale databases, the MOF community has witnessed innovations brought by data-driven machine learning methods, which have enabled a deeper understanding of the chemical nature of MOFs and led to the development of novel structures. Notably, machine learning is continuously and rapidly advancing as new methodologies, architectures, and data representations are actively being investigated, and their implementation in materials discovery is vigorously pursued. Under these circumstances, it is important to closely monitor recent research trends and identify the technologies that are being introduced. In this Perspective, we focus on emerging trends of machine learning within the field of MOFs, the challenges they face, and the future directions of their development.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214357","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}
Site-selective C–H borylation is an important strategy for constructing molecular diversity in arenes and heteroarenes. Although transition-metal-catalyzed borylation is well explored, developing metal-free strategies remains scarce. Herein, we developed a straightforward approach for BBr3-mediated selective C–H borylation of naphthamide and phenyl acetamide derivatives under metal-free conditions. This methodology appears to be economical and cost-effective. Successful borylation of drug molecules such as ibuprofen and indoprofen demonstrates the versatility and utility of this metal-free borylation. An exclusive monoselectivity was observed without a trace of diboration. Despite the possibility of forming a 5-membered boronated intermediate at the ortho-position, the selectively 6-membered intermediate paved the way for the formation of the peri-product, which was further supported by detailed computational investigation.
{"title":"Metal-free Borylation of α-Naphthamides and Phenylacetic Acid Drug","authors":"Suman Maji, Parveen Rawal, Animesh Ghosh, Karishma Pidiyar, Shaeel A. Al-Thabaiti, Puneet Gupta, Debabrata Maiti","doi":"10.1021/jacsau.4c00660","DOIUrl":"https://doi.org/10.1021/jacsau.4c00660","url":null,"abstract":"Site-selective C–H borylation is an important strategy for constructing molecular diversity in arenes and heteroarenes. Although transition-metal-catalyzed borylation is well explored, developing metal-free strategies remains scarce. Herein, we developed a straightforward approach for BBr<sub>3</sub>-mediated selective C–H borylation of naphthamide and phenyl acetamide derivatives under metal-free conditions. This methodology appears to be economical and cost-effective. Successful borylation of drug molecules such as ibuprofen and indoprofen demonstrates the versatility and utility of this metal-free borylation. An exclusive monoselectivity was observed without a trace of diboration. Despite the possibility of forming a 5-membered boronated intermediate at the <i>ortho</i>-position, the selectively 6-membered intermediate paved the way for the formation of the peri-product, which was further supported by detailed computational investigation.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214359","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}
Ismael Compañón, Collin J. Ballard, Erandi Lira-Navarrete, Tanausú Santos, Serena Monaco, Juan C. Muñoz-García, Ignacio Delso, Jesus Angulo, Thomas A. Gerken, Katrine T. Schjoldager, Henrik Clausen, Tomás Tejero, Pedro Merino, Francisco Corzana, Ramon Hurtado-Guerrero, Mattia Ghirardello
The GalNAc-transferase (GalNAc-T) family, consisting of 20 isoenzymes, regulates the O-glycosylation process of mucin glycopeptides by transferring GalNAc units to serine/threonine residues. Dysregulation of specific GalNAc-Ts is associated with various diseases, making these enzymes attractive targets for drug development. The development of inhibitors is key to understanding the implications of GalNAc-Ts in human diseases. However, developing selective inhibitors for individual GalNAc-Ts represents a major challenge due to shared structural similarities among the isoenzymes and some degree of redundancy among the natural substrates. Herein, we report the development of a GalNAc-T2 inhibitor with higher potency compared to those of the T1 and T3 isoforms. The most promising candidate features bivalent GalNAc and thiophene moieties on a peptide chain, enabling binding to both the lectin and catalytic domains of the enzyme. The binding mode was confirmed by competitive saturation transfer difference NMR experiments and validated through molecular dynamics simulations. The inhibitor demonstrated an IC50 of 21.4 μM for GalNAc-T2, with 8- and 32-fold higher selectivity over the T3 and T1 isoforms, respectively, representing a significant step forward in the synthesis of specific GalNAc-T inhibitors tailored to the unique structural features of the targeted isoform.
{"title":"Rational Design of Dual-Domain Binding Inhibitors for N-Acetylgalactosamine Transferase 2 with Improved Selectivity over the T1 and T3 Isoforms","authors":"Ismael Compañón, Collin J. Ballard, Erandi Lira-Navarrete, Tanausú Santos, Serena Monaco, Juan C. Muñoz-García, Ignacio Delso, Jesus Angulo, Thomas A. Gerken, Katrine T. Schjoldager, Henrik Clausen, Tomás Tejero, Pedro Merino, Francisco Corzana, Ramon Hurtado-Guerrero, Mattia Ghirardello","doi":"10.1021/jacsau.4c00633","DOIUrl":"https://doi.org/10.1021/jacsau.4c00633","url":null,"abstract":"The GalNAc-transferase (GalNAc-T) family, consisting of 20 isoenzymes, regulates the <i>O</i>-glycosylation process of mucin glycopeptides by transferring GalNAc units to serine/threonine residues. Dysregulation of specific GalNAc-Ts is associated with various diseases, making these enzymes attractive targets for drug development. The development of inhibitors is key to understanding the implications of GalNAc-Ts in human diseases. However, developing selective inhibitors for individual GalNAc-Ts represents a major challenge due to shared structural similarities among the isoenzymes and some degree of redundancy among the natural substrates. Herein, we report the development of a GalNAc-T2 inhibitor with higher potency compared to those of the T1 and T3 isoforms. The most promising candidate features bivalent GalNAc and thiophene moieties on a peptide chain, enabling binding to both the lectin and catalytic domains of the enzyme. The binding mode was confirmed by competitive saturation transfer difference NMR experiments and validated through molecular dynamics simulations. The inhibitor demonstrated an IC<sub>50</sub> of 21.4 μM for GalNAc-T2, with 8- and 32-fold higher selectivity over the T3 and T1 isoforms, respectively, representing a significant step forward in the synthesis of specific GalNAc-T inhibitors tailored to the unique structural features of the targeted isoform.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214358","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}
Trioxacarcin A (TXN) is a highly potent cytotoxic antibiotic with remarkable structural complexity. The crystal structure of TXN bound to double-stranded DNA (dsDNA) suggested that the TXN interaction might depend on positions of two sugar subunits on the minor and major grooves of dsDNA. LL-D49194α1 (LLD) is a TXN analogue bearing the same polycyclic polyketide scaffold with a distinct glycosylation pattern. Although LLD was in a phase I clinical trial, how LLD binds to dsDNA remains unclear. Here, we solved the solution structures at high resolutions of palindromic 2″-fluorine-labeled guanine-containing duplex d(A1A2C3C4GFGFT7T8)2 and of its stable LLD and TXN covalently bound complexes. Combined with biochemical assays, we found that TXN-alkylated dsDNA would tend to keep DNA helix conformation, while LLD-alkylated dsDNA lost its stability more than TXN-alkylated dsDNA, leading to dsDNA denaturation. Thus, despite lower cytotoxicity in vitro, the differences of sugar substitutions in LLD caused greater DNA damage than TXN, thereby bringing about a completely new biological effect.
{"title":"Different DNA Binding and Damage Mode between Anticancer Antibiotics Trioxacarcin A and LL-D49194α1","authors":"Ruo-Qin Gao, Xiao-Dong Hu, Qiang Zhou, Xian-Feng Hou, Chunyang Cao, Gong-Li Tang","doi":"10.1021/jacsau.4c00611","DOIUrl":"https://doi.org/10.1021/jacsau.4c00611","url":null,"abstract":"Trioxacarcin A (TXN) is a highly potent cytotoxic antibiotic with remarkable structural complexity. The crystal structure of TXN bound to double-stranded DNA (dsDNA) suggested that the TXN interaction might depend on positions of two sugar subunits on the minor and major grooves of dsDNA. LL-D49194α1 (LLD) is a TXN analogue bearing the same polycyclic polyketide scaffold with a distinct glycosylation pattern. Although LLD was in a phase I clinical trial, how LLD binds to dsDNA remains unclear. Here, we solved the solution structures at high resolutions of palindromic 2″-fluorine-labeled guanine-containing duplex d(A<sub>1</sub>A<sub>2</sub>C<sub>3</sub>C<sub>4</sub>G<sup>F</sup>G<sup>F</sup>T<sub>7</sub>T<sub>8</sub>)<sub>2</sub> and of its stable LLD and TXN covalently bound complexes. Combined with biochemical assays, we found that TXN-alkylated dsDNA would tend to keep DNA helix conformation, while LLD-alkylated dsDNA lost its stability more than TXN-alkylated dsDNA, leading to dsDNA denaturation. Thus, despite lower cytotoxicity in vitro, the differences of sugar substitutions in LLD caused greater DNA damage than TXN, thereby bringing about a completely new biological effect.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214360","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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