Pub Date : 2025-03-25DOI: 10.1021/acs.accounts.5c0000310.1021/acs.accounts.5c00003
Shipeng He, Guoqiang Dong and Chunquan Sheng*,
<p >Targeted protein degradation (TPD) technologies, exemplified by proteolysis-targeting chimeras (PROTACs), have revolutionized therapeutic strategies by facilitating the selective degradation of pathogenic proteins instead of simply inhibiting their functions. This degradation-based strategy offers significant advantages over traditional small-molecule inhibitors, which often block protein activity without eliminating the target. PROTACs function by leveraging the ubiquitin-proteasome system to selectively degrade target proteins, thus enabling the modulation of a broader range of disease-causing proteins including those that were previously considered undruggable. As a result, PROTAC-based therapies have gained considerable attention in drug discovery, especially in oncology, immunology, and neurodegenerative diseases. However, clinical translation of conventional PROTACs remains challenging due to issues such as limited target specificity, poor solubility, inadequate cellular permeability, unfavorable pharmacokinetic profiles, and the absence of spatiotemporal resolution.</p><p >To address these hurdles, various innovative strategies have been developed to enhance the precision of protein degradation. These approaches focus on improving targeted delivery, solubility, membrane permeability, and spatiotemporal control with the goal of overcoming the inherent limitations of traditional PROTAC designs. For instance, aptamer-conjugated PROTACs have shown great promise by improving tumor selectivity and reducing off-target effects through tumor-specific receptor recognition and subsequent internalization. Moreover, the development of drugtamer-PROTAC conjugates enables more precise codelivery with small-molecule agents, optimizing the synergistic effects of both modalities while minimizing systemic toxicity. Additionally, RGD peptide-based PROTAC conjugation strategies capitalize on the use of tumor-homing peptides to enhance cellular uptake, improve tumor penetration, and increase degradation specificity in tumor cells, further reducing off-target toxicities in healthy tissues.</p><p >Another critical advancement is the development of photocontrolled PROTACs, which allow for precise temporal regulation of protein degradation <i>in vivo</i>. By leveraging light-responsive molecules, these systems provide the ability to trigger protein degradation at specific time points, offering unparalleled control over therapeutic interventions. Furthermore, theranostic PROTACs, which combine both diagnostic and therapeutic functions, facilitate real-time monitoring of protein degradation events in living cells and animal models, enabling simultaneous assessment of the therapeutic efficacy and biomarker visualization.</p><p >This Account reviews recent advancements in the design of smart PROTACs, highlighting strategies that improve their tumor specificity, solubility, permeability, and spatiotemporal control. These innovations provide promising solutions to a
{"title":"Strategies for Precise Modulation of Protein Degradation","authors":"Shipeng He, Guoqiang Dong and Chunquan Sheng*, ","doi":"10.1021/acs.accounts.5c0000310.1021/acs.accounts.5c00003","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00003https://doi.org/10.1021/acs.accounts.5c00003","url":null,"abstract":"<p >Targeted protein degradation (TPD) technologies, exemplified by proteolysis-targeting chimeras (PROTACs), have revolutionized therapeutic strategies by facilitating the selective degradation of pathogenic proteins instead of simply inhibiting their functions. This degradation-based strategy offers significant advantages over traditional small-molecule inhibitors, which often block protein activity without eliminating the target. PROTACs function by leveraging the ubiquitin-proteasome system to selectively degrade target proteins, thus enabling the modulation of a broader range of disease-causing proteins including those that were previously considered undruggable. As a result, PROTAC-based therapies have gained considerable attention in drug discovery, especially in oncology, immunology, and neurodegenerative diseases. However, clinical translation of conventional PROTACs remains challenging due to issues such as limited target specificity, poor solubility, inadequate cellular permeability, unfavorable pharmacokinetic profiles, and the absence of spatiotemporal resolution.</p><p >To address these hurdles, various innovative strategies have been developed to enhance the precision of protein degradation. These approaches focus on improving targeted delivery, solubility, membrane permeability, and spatiotemporal control with the goal of overcoming the inherent limitations of traditional PROTAC designs. For instance, aptamer-conjugated PROTACs have shown great promise by improving tumor selectivity and reducing off-target effects through tumor-specific receptor recognition and subsequent internalization. Moreover, the development of drugtamer-PROTAC conjugates enables more precise codelivery with small-molecule agents, optimizing the synergistic effects of both modalities while minimizing systemic toxicity. Additionally, RGD peptide-based PROTAC conjugation strategies capitalize on the use of tumor-homing peptides to enhance cellular uptake, improve tumor penetration, and increase degradation specificity in tumor cells, further reducing off-target toxicities in healthy tissues.</p><p >Another critical advancement is the development of photocontrolled PROTACs, which allow for precise temporal regulation of protein degradation <i>in vivo</i>. By leveraging light-responsive molecules, these systems provide the ability to trigger protein degradation at specific time points, offering unparalleled control over therapeutic interventions. Furthermore, theranostic PROTACs, which combine both diagnostic and therapeutic functions, facilitate real-time monitoring of protein degradation events in living cells and animal models, enabling simultaneous assessment of the therapeutic efficacy and biomarker visualization.</p><p >This Account reviews recent advancements in the design of smart PROTACs, highlighting strategies that improve their tumor specificity, solubility, permeability, and spatiotemporal control. These innovations provide promising solutions to a","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1236–1248 1236–1248"},"PeriodicalIF":16.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-25DOI: 10.1021/acs.accounts.5c0008110.1021/acs.accounts.5c00081
Huangtianzhi Zhu, Natasha M. A. Speakman, Tanya K. Ronson and Jonathan R. Nitschke*,
<p >Coordination cages formed via subcomponent self-assembly have found applications in fields including separation, sensing, catalysis, and the stabilization of reactive species, due to their guest binding abilities. Subcomponent self-assembly, which combines dynamic covalent bond (C═N) formation and reversible metal coordination (N→Metal), has enabled the preparation of many intricate polyhedral structures with minimal synthetic effort. This method has been used to prepare multitopic pyridyl-imine ligands that form the edges or faces of polyhedra, with octahedral metal ions, including Fe<sup>II</sup>, Co<sup>II</sup>, and Zn<sup>II</sup>, defining the vertices. The use of Cu<sup>I</sup> in subcomponent self-assembly is less widely reported, as the tetrahedral coordination geometry of Cu<sup>I</sup> requires only two bidentate ligands, which can lead to lower-nuclearity assemblies instead of three-dimensional cages. The coordination flexibility of Cu<sup>I</sup> also adds a challenge to the fabrication of well-defined nanostructures. This Account summarizes a series of higher-order Cu<sup>I</sup>-based coordination cages and the design principles derived from their syntheses. Starting with the development of Cu<sup>I</sup> assemblies and the challenges of preparing Cu<sup>I</sup> cages, we discuss the circumvention of oligomer formation and control of the self-assembly process with Cu<sup>I</sup> through (i) ligand engineering, (ii) vertex design, and (iii) guest-induced structural transformations. Aromatic stacking between corranulene-containing ligands is exploited to produce a 5-fold interlocked [2]catenane, whereas the incorporation of a sterically hindered triptycene subcomponent that minimizes aromatic stacking produces a double-octahedron and a hexagonal prism. These structures illustrate the importance of ligand engineering for obtaining complex Cu<sup>I</sup> structures. We also explored the formation of cages with homo- or heterobimetallic vertices via two distinct strategies. First, dicopper(I) helicates were employed as cage vertices, and second, subcomponents with nonconverging coordination vectors were used. Such bimetallic vertices are challenging to incorporate when octahedral metal templates are used, but the flexibility of Cu<sup>I</sup> renders them accessible. The closed-shell electronic configuration of Cu<sup>I</sup> can endow the cages with photoluminescence, providing circularly polarized luminescence in the presence of helicity-enriched dicopper(I) vertices. The flexible coordination sphere of Cu<sup>I</sup> also facilitates structural transformations upon the addition of suitable guests. One such system is able to self-sort to express the most thermodynamically stable host–guest complex and also undergo structural changes in response to different temperatures and solvents. The insights gained about the structural bases of these Cu<sup>I</sup> cages may help enable the design of other novel Cu<sup>I</sup> nanostructures
{"title":"Higher-Order CuI-Based Cages via Subcomponent Self-Assembly","authors":"Huangtianzhi Zhu, Natasha M. A. Speakman, Tanya K. Ronson and Jonathan R. Nitschke*, ","doi":"10.1021/acs.accounts.5c0008110.1021/acs.accounts.5c00081","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00081https://doi.org/10.1021/acs.accounts.5c00081","url":null,"abstract":"<p >Coordination cages formed via subcomponent self-assembly have found applications in fields including separation, sensing, catalysis, and the stabilization of reactive species, due to their guest binding abilities. Subcomponent self-assembly, which combines dynamic covalent bond (C═N) formation and reversible metal coordination (N→Metal), has enabled the preparation of many intricate polyhedral structures with minimal synthetic effort. This method has been used to prepare multitopic pyridyl-imine ligands that form the edges or faces of polyhedra, with octahedral metal ions, including Fe<sup>II</sup>, Co<sup>II</sup>, and Zn<sup>II</sup>, defining the vertices. The use of Cu<sup>I</sup> in subcomponent self-assembly is less widely reported, as the tetrahedral coordination geometry of Cu<sup>I</sup> requires only two bidentate ligands, which can lead to lower-nuclearity assemblies instead of three-dimensional cages. The coordination flexibility of Cu<sup>I</sup> also adds a challenge to the fabrication of well-defined nanostructures. This Account summarizes a series of higher-order Cu<sup>I</sup>-based coordination cages and the design principles derived from their syntheses. Starting with the development of Cu<sup>I</sup> assemblies and the challenges of preparing Cu<sup>I</sup> cages, we discuss the circumvention of oligomer formation and control of the self-assembly process with Cu<sup>I</sup> through (i) ligand engineering, (ii) vertex design, and (iii) guest-induced structural transformations. Aromatic stacking between corranulene-containing ligands is exploited to produce a 5-fold interlocked [2]catenane, whereas the incorporation of a sterically hindered triptycene subcomponent that minimizes aromatic stacking produces a double-octahedron and a hexagonal prism. These structures illustrate the importance of ligand engineering for obtaining complex Cu<sup>I</sup> structures. We also explored the formation of cages with homo- or heterobimetallic vertices via two distinct strategies. First, dicopper(I) helicates were employed as cage vertices, and second, subcomponents with nonconverging coordination vectors were used. Such bimetallic vertices are challenging to incorporate when octahedral metal templates are used, but the flexibility of Cu<sup>I</sup> renders them accessible. The closed-shell electronic configuration of Cu<sup>I</sup> can endow the cages with photoluminescence, providing circularly polarized luminescence in the presence of helicity-enriched dicopper(I) vertices. The flexible coordination sphere of Cu<sup>I</sup> also facilitates structural transformations upon the addition of suitable guests. One such system is able to self-sort to express the most thermodynamically stable host–guest complex and also undergo structural changes in response to different temperatures and solvents. The insights gained about the structural bases of these Cu<sup>I</sup> cages may help enable the design of other novel Cu<sup>I</sup> nanostructures ","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1296–1307 1296–1307"},"PeriodicalIF":16.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.accounts.5c00081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-25DOI: 10.1021/acs.accounts.5c00081
Huangtianzhi Zhu, Natasha M A Speakman, Tanya K Ronson, Jonathan R Nitschke
<p><p>ConspectusCoordination cages formed via subcomponent self-assembly have found applications in fields including separation, sensing, catalysis, and the stabilization of reactive species, due to their guest binding abilities. Subcomponent self-assembly, which combines dynamic covalent bond (C═N) formation and reversible metal coordination (N→Metal), has enabled the preparation of many intricate polyhedral structures with minimal synthetic effort. This method has been used to prepare multitopic pyridyl-imine ligands that form the edges or faces of polyhedra, with octahedral metal ions, including Fe<sup>II</sup>, Co<sup>II</sup>, and Zn<sup>II</sup>, defining the vertices. The use of Cu<sup>I</sup> in subcomponent self-assembly is less widely reported, as the tetrahedral coordination geometry of Cu<sup>I</sup> requires only two bidentate ligands, which can lead to lower-nuclearity assemblies instead of three-dimensional cages. The coordination flexibility of Cu<sup>I</sup> also adds a challenge to the fabrication of well-defined nanostructures. This Account summarizes a series of higher-order Cu<sup>I</sup>-based coordination cages and the design principles derived from their syntheses. Starting with the development of Cu<sup>I</sup> assemblies and the challenges of preparing Cu<sup>I</sup> cages, we discuss the circumvention of oligomer formation and control of the self-assembly process with Cu<sup>I</sup> through (i) ligand engineering, (ii) vertex design, and (iii) guest-induced structural transformations. Aromatic stacking between corranulene-containing ligands is exploited to produce a 5-fold interlocked [2]catenane, whereas the incorporation of a sterically hindered triptycene subcomponent that minimizes aromatic stacking produces a double-octahedron and a hexagonal prism. These structures illustrate the importance of ligand engineering for obtaining complex Cu<sup>I</sup> structures. We also explored the formation of cages with homo- or heterobimetallic vertices via two distinct strategies. First, dicopper(I) helicates were employed as cage vertices, and second, subcomponents with nonconverging coordination vectors were used. Such bimetallic vertices are challenging to incorporate when octahedral metal templates are used, but the flexibility of Cu<sup>I</sup> renders them accessible. The closed-shell electronic configuration of Cu<sup>I</sup> can endow the cages with photoluminescence, providing circularly polarized luminescence in the presence of helicity-enriched dicopper(I) vertices. The flexible coordination sphere of Cu<sup>I</sup> also facilitates structural transformations upon the addition of suitable guests. One such system is able to self-sort to express the most thermodynamically stable host-guest complex and also undergo structural changes in response to different temperatures and solvents. The insights gained about the structural bases of these Cu<sup>I</sup> cages may help enable the design of other novel Cu<sup>I</sup> nan
{"title":"Higher-Order Cu<sup>I</sup>-Based Cages via Subcomponent Self-Assembly.","authors":"Huangtianzhi Zhu, Natasha M A Speakman, Tanya K Ronson, Jonathan R Nitschke","doi":"10.1021/acs.accounts.5c00081","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00081","url":null,"abstract":"<p><p>ConspectusCoordination cages formed via subcomponent self-assembly have found applications in fields including separation, sensing, catalysis, and the stabilization of reactive species, due to their guest binding abilities. Subcomponent self-assembly, which combines dynamic covalent bond (C═N) formation and reversible metal coordination (N→Metal), has enabled the preparation of many intricate polyhedral structures with minimal synthetic effort. This method has been used to prepare multitopic pyridyl-imine ligands that form the edges or faces of polyhedra, with octahedral metal ions, including Fe<sup>II</sup>, Co<sup>II</sup>, and Zn<sup>II</sup>, defining the vertices. The use of Cu<sup>I</sup> in subcomponent self-assembly is less widely reported, as the tetrahedral coordination geometry of Cu<sup>I</sup> requires only two bidentate ligands, which can lead to lower-nuclearity assemblies instead of three-dimensional cages. The coordination flexibility of Cu<sup>I</sup> also adds a challenge to the fabrication of well-defined nanostructures. This Account summarizes a series of higher-order Cu<sup>I</sup>-based coordination cages and the design principles derived from their syntheses. Starting with the development of Cu<sup>I</sup> assemblies and the challenges of preparing Cu<sup>I</sup> cages, we discuss the circumvention of oligomer formation and control of the self-assembly process with Cu<sup>I</sup> through (i) ligand engineering, (ii) vertex design, and (iii) guest-induced structural transformations. Aromatic stacking between corranulene-containing ligands is exploited to produce a 5-fold interlocked [2]catenane, whereas the incorporation of a sterically hindered triptycene subcomponent that minimizes aromatic stacking produces a double-octahedron and a hexagonal prism. These structures illustrate the importance of ligand engineering for obtaining complex Cu<sup>I</sup> structures. We also explored the formation of cages with homo- or heterobimetallic vertices via two distinct strategies. First, dicopper(I) helicates were employed as cage vertices, and second, subcomponents with nonconverging coordination vectors were used. Such bimetallic vertices are challenging to incorporate when octahedral metal templates are used, but the flexibility of Cu<sup>I</sup> renders them accessible. The closed-shell electronic configuration of Cu<sup>I</sup> can endow the cages with photoluminescence, providing circularly polarized luminescence in the presence of helicity-enriched dicopper(I) vertices. The flexible coordination sphere of Cu<sup>I</sup> also facilitates structural transformations upon the addition of suitable guests. One such system is able to self-sort to express the most thermodynamically stable host-guest complex and also undergo structural changes in response to different temperatures and solvents. The insights gained about the structural bases of these Cu<sup>I</sup> cages may help enable the design of other novel Cu<sup>I</sup> nan","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-24DOI: 10.1021/acs.accounts.5c00069
Shu-Qi Wu, Sheng-Qun Su, Shinji Kanegawa, Osamu Sato
<p><p>ConspectusCompounds with polarization switching properties have a wide range of applications including ferroelectric memories, pyroelectric sensors, and piezoelectric actuators. Ferroelectric compounds are primarily focused owing to their ability to switch between two or more symmetry-equivalent polarization states. Besides ferroelectrics, numerous compounds with polar structures exhibit polarization changes in response to external stimuli such as temperature and pressure; however, such effects are normally too small to be considered in practical applications.Recently, we proposed a strategy to achieve polarization switching via electron transfer in polar crystals. The strategy consists of the synthesis of molecules exhibiting intramolecular electron transfer, combined with crystal engineering to align these molecules so that the molecular dipole moments are not canceled at the lattice level. Consequently, vectorial (or directional) electron transfer results in a significant polarization change comparable to what is found for conventional ferroelectrics. Chemically, since the functional motifs are molecules, operational parameters such as the working temperatures and polarization change can be fine-tuned by adjusting the energy levels of the electron donor and acceptor sites and their separation, which enables a more active control of polarization than ferroelectrics. From a physical perspective, the key difference between these systems and ferroelectrics is that the polarization switching occurs between symmetry inequivalent and nondegenerate polar states. As a direct result, they can be switched by various external stimuli other than electric fields, including temperature, magnetic fields, pressure, and light, owing to their different physical properties such as entropy, magnetization, volume, absorption, etc. Moreover, although thermally- and photoinduced ferroelectrics have been reported, they typically form domain structures with different polarization direction due to a symmetry-related degenerate ground state, causing macroscopic polarization to be largely canceled. In contrast, our compounds, which lack accessible symmetry equivalent states, can achieve a perfect polarization alignment without polarization domains upon temperature changes, photoirradiation, or magnetic field.In this Account, we discuss the synthesis of polarization switching compounds, i.e., dinuclear [CoGa], [FeCo], and [CrCo] complexes, via a chirality-assisted method. The thermally induced polarization switching behavior, or pyroelectric effect, is then explained, highlighting the large polarization change (2.9 μC cm<sup>-2</sup>) in the [CoGa] complex, which is comparable to the widely used infrared (IR) detector material, triglycine sulfate (TGS). We then discuss the optical polarization memory effect and photoenergy conversion properties, which are a consequence of the photoinduced valence tautomeric behavior with a long-lived photoinduced metastable state. Fu
{"title":"Active Polarization Engineering between Symmetry Inequivalent Polar States Using Electron Transfer: A Nonferroelectric Approach.","authors":"Shu-Qi Wu, Sheng-Qun Su, Shinji Kanegawa, Osamu Sato","doi":"10.1021/acs.accounts.5c00069","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00069","url":null,"abstract":"<p><p>ConspectusCompounds with polarization switching properties have a wide range of applications including ferroelectric memories, pyroelectric sensors, and piezoelectric actuators. Ferroelectric compounds are primarily focused owing to their ability to switch between two or more symmetry-equivalent polarization states. Besides ferroelectrics, numerous compounds with polar structures exhibit polarization changes in response to external stimuli such as temperature and pressure; however, such effects are normally too small to be considered in practical applications.Recently, we proposed a strategy to achieve polarization switching via electron transfer in polar crystals. The strategy consists of the synthesis of molecules exhibiting intramolecular electron transfer, combined with crystal engineering to align these molecules so that the molecular dipole moments are not canceled at the lattice level. Consequently, vectorial (or directional) electron transfer results in a significant polarization change comparable to what is found for conventional ferroelectrics. Chemically, since the functional motifs are molecules, operational parameters such as the working temperatures and polarization change can be fine-tuned by adjusting the energy levels of the electron donor and acceptor sites and their separation, which enables a more active control of polarization than ferroelectrics. From a physical perspective, the key difference between these systems and ferroelectrics is that the polarization switching occurs between symmetry inequivalent and nondegenerate polar states. As a direct result, they can be switched by various external stimuli other than electric fields, including temperature, magnetic fields, pressure, and light, owing to their different physical properties such as entropy, magnetization, volume, absorption, etc. Moreover, although thermally- and photoinduced ferroelectrics have been reported, they typically form domain structures with different polarization direction due to a symmetry-related degenerate ground state, causing macroscopic polarization to be largely canceled. In contrast, our compounds, which lack accessible symmetry equivalent states, can achieve a perfect polarization alignment without polarization domains upon temperature changes, photoirradiation, or magnetic field.In this Account, we discuss the synthesis of polarization switching compounds, i.e., dinuclear [CoGa], [FeCo], and [CrCo] complexes, via a chirality-assisted method. The thermally induced polarization switching behavior, or pyroelectric effect, is then explained, highlighting the large polarization change (2.9 μC cm<sup>-2</sup>) in the [CoGa] complex, which is comparable to the widely used infrared (IR) detector material, triglycine sulfate (TGS). We then discuss the optical polarization memory effect and photoenergy conversion properties, which are a consequence of the photoinduced valence tautomeric behavior with a long-lived photoinduced metastable state. Fu","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-24DOI: 10.1021/acs.accounts.5c0006910.1021/acs.accounts.5c00069
Shu-Qi Wu, Sheng-Qun Su, Shinji Kanegawa and Osamu Sato*,
<p >Compounds with polarization switching properties have a wide range of applications including ferroelectric memories, pyroelectric sensors, and piezoelectric actuators. Ferroelectric compounds are primarily focused owing to their ability to switch between two or more symmetry-equivalent polarization states. Besides ferroelectrics, numerous compounds with polar structures exhibit polarization changes in response to external stimuli such as temperature and pressure; however, such effects are normally too small to be considered in practical applications.</p><p >Recently, we proposed a strategy to achieve polarization switching via electron transfer in polar crystals. The strategy consists of the synthesis of molecules exhibiting intramolecular electron transfer, combined with crystal engineering to align these molecules so that the molecular dipole moments are not canceled at the lattice level. Consequently, vectorial (or directional) electron transfer results in a significant polarization change comparable to what is found for conventional ferroelectrics. Chemically, since the functional motifs are molecules, operational parameters such as the working temperatures and polarization change can be fine-tuned by adjusting the energy levels of the electron donor and acceptor sites and their separation, which enables a more active control of polarization than ferroelectrics. From a physical perspective, the key difference between these systems and ferroelectrics is that the polarization switching occurs between symmetry inequivalent and nondegenerate polar states. As a direct result, they can be switched by various external stimuli other than electric fields, including temperature, magnetic fields, pressure, and light, owing to their different physical properties such as entropy, magnetization, volume, absorption, etc. Moreover, although thermally- and photoinduced ferroelectrics have been reported, they typically form domain structures with different polarization direction due to a symmetry-related degenerate ground state, causing macroscopic polarization to be largely canceled. In contrast, our compounds, which lack accessible symmetry equivalent states, can achieve a perfect polarization alignment without polarization domains upon temperature changes, photoirradiation, or magnetic field.</p><p >In this Account, we discuss the synthesis of polarization switching compounds, i.e., dinuclear [CoGa], [FeCo], and [CrCo] complexes, via a chirality-assisted method. The thermally induced polarization switching behavior, or pyroelectric effect, is then explained, highlighting the large polarization change (2.9 μC cm<sup>–2</sup>) in the [CoGa] complex, which is comparable to the widely used infrared (IR) detector material, triglycine sulfate (TGS). We then discuss the optical polarization memory effect and photoenergy conversion properties, which are a consequence of the photoinduced valence tautomeric behavior with a long-lived photoinduced metastable state
{"title":"Active Polarization Engineering between Symmetry Inequivalent Polar States Using Electron Transfer: A Nonferroelectric Approach","authors":"Shu-Qi Wu, Sheng-Qun Su, Shinji Kanegawa and Osamu Sato*, ","doi":"10.1021/acs.accounts.5c0006910.1021/acs.accounts.5c00069","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00069https://doi.org/10.1021/acs.accounts.5c00069","url":null,"abstract":"<p >Compounds with polarization switching properties have a wide range of applications including ferroelectric memories, pyroelectric sensors, and piezoelectric actuators. Ferroelectric compounds are primarily focused owing to their ability to switch between two or more symmetry-equivalent polarization states. Besides ferroelectrics, numerous compounds with polar structures exhibit polarization changes in response to external stimuli such as temperature and pressure; however, such effects are normally too small to be considered in practical applications.</p><p >Recently, we proposed a strategy to achieve polarization switching via electron transfer in polar crystals. The strategy consists of the synthesis of molecules exhibiting intramolecular electron transfer, combined with crystal engineering to align these molecules so that the molecular dipole moments are not canceled at the lattice level. Consequently, vectorial (or directional) electron transfer results in a significant polarization change comparable to what is found for conventional ferroelectrics. Chemically, since the functional motifs are molecules, operational parameters such as the working temperatures and polarization change can be fine-tuned by adjusting the energy levels of the electron donor and acceptor sites and their separation, which enables a more active control of polarization than ferroelectrics. From a physical perspective, the key difference between these systems and ferroelectrics is that the polarization switching occurs between symmetry inequivalent and nondegenerate polar states. As a direct result, they can be switched by various external stimuli other than electric fields, including temperature, magnetic fields, pressure, and light, owing to their different physical properties such as entropy, magnetization, volume, absorption, etc. Moreover, although thermally- and photoinduced ferroelectrics have been reported, they typically form domain structures with different polarization direction due to a symmetry-related degenerate ground state, causing macroscopic polarization to be largely canceled. In contrast, our compounds, which lack accessible symmetry equivalent states, can achieve a perfect polarization alignment without polarization domains upon temperature changes, photoirradiation, or magnetic field.</p><p >In this Account, we discuss the synthesis of polarization switching compounds, i.e., dinuclear [CoGa], [FeCo], and [CrCo] complexes, via a chirality-assisted method. The thermally induced polarization switching behavior, or pyroelectric effect, is then explained, highlighting the large polarization change (2.9 μC cm<sup>–2</sup>) in the [CoGa] complex, which is comparable to the widely used infrared (IR) detector material, triglycine sulfate (TGS). We then discuss the optical polarization memory effect and photoenergy conversion properties, which are a consequence of the photoinduced valence tautomeric behavior with a long-lived photoinduced metastable state","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1284–1295 1284–1295"},"PeriodicalIF":16.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-19DOI: 10.1021/acs.accounts.4c0079610.1021/acs.accounts.4c00796
Xin Liu, Binbin Hu and Zhilin Yu*,
<p >Emulating the structural features or functions of natural systems has been demonstrated as a state-of-the-art strategy to create artificial functional materials. Inspired by the assembly and bioactivity of proteins, the self-assembly of peptides into nanostructures represents a promising approach for creating biomaterials. Conventional assembled peptide biomaterials are typically formulated in solution and delivered to pathological sites for implementing theranostic objectives. However, this translocation entails a switch from formulation conditions to the physiological environment and raises concerns about material performance. In addition, the precise and efficient accumulation of administered biomaterials at target sites remains a significant challenge, leading to potential biosafety issues associated with off-target effects. These limitations significantly hinder the progress of advanced biomaterials. To address these concerns, the past few years have witnessed the development of in situ assembly of peptides in living systems as a new endeavor for optimizing biomaterial performance benefiting from the advances of stimuli-responsive reactions regulating noncovalent interactions. In situ assembly of peptides refers to the processes of regulating assembly via stimuli-responsive reactions at target sites. Due to the advantages of precisely forming well-defined nanostructures at pathological lesions, in situ-formed assemblies with integrated bioactivity are interesting for the development of next-generation biomedical agents.</p><p >Despite the great potential of in situ assembly of peptides for developing biomedical agents, this research area still suffers from a limited toolkit for operating peptide assembly under complicated physiological conditions. Considering the advantages of amino acids in being incorporated into peptide backbones and modified with stimuli-responsive units, development of an amino acid toolkit is promising to address this concern. Therefore, our laboratory has been intensively engaged in designing and discovering stimuli-responsive noncanonical amino acids (ncAAs) to expand the toolkit for manipulating peptide assembly under various biological conditions. Thus far, we have synthesized peptides containing ncAAs 4-aminoproline, 2-nitroimidazole alanine, Se-methionine, sulfated tyrosine, and glycosylated serine, which allow us to develop acid-responsive, redox-responsive, and enzyme-responsive assembly systems. Based on these stimuli-responsive ncAAs, we have established complex self-sorting assembly, self-amplified assembly, and dissipative assembly systems in living cells to optimize the bioactivity of peptides. The resulting in situ assembly systems exhibit morphological adaptability to the biological microenvironment, which contributes to overcoming delivery barriers and improvement of targeting accumulation. Therefore, by utilizing the developed toolkit, we have further created supramolecular PROTACs, supramolecula
{"title":"Noncanonical Amino Acids Dictate Peptide Assembly in Living Cells","authors":"Xin Liu, Binbin Hu and Zhilin Yu*, ","doi":"10.1021/acs.accounts.4c0079610.1021/acs.accounts.4c00796","DOIUrl":"https://doi.org/10.1021/acs.accounts.4c00796https://doi.org/10.1021/acs.accounts.4c00796","url":null,"abstract":"<p >Emulating the structural features or functions of natural systems has been demonstrated as a state-of-the-art strategy to create artificial functional materials. Inspired by the assembly and bioactivity of proteins, the self-assembly of peptides into nanostructures represents a promising approach for creating biomaterials. Conventional assembled peptide biomaterials are typically formulated in solution and delivered to pathological sites for implementing theranostic objectives. However, this translocation entails a switch from formulation conditions to the physiological environment and raises concerns about material performance. In addition, the precise and efficient accumulation of administered biomaterials at target sites remains a significant challenge, leading to potential biosafety issues associated with off-target effects. These limitations significantly hinder the progress of advanced biomaterials. To address these concerns, the past few years have witnessed the development of in situ assembly of peptides in living systems as a new endeavor for optimizing biomaterial performance benefiting from the advances of stimuli-responsive reactions regulating noncovalent interactions. In situ assembly of peptides refers to the processes of regulating assembly via stimuli-responsive reactions at target sites. Due to the advantages of precisely forming well-defined nanostructures at pathological lesions, in situ-formed assemblies with integrated bioactivity are interesting for the development of next-generation biomedical agents.</p><p >Despite the great potential of in situ assembly of peptides for developing biomedical agents, this research area still suffers from a limited toolkit for operating peptide assembly under complicated physiological conditions. Considering the advantages of amino acids in being incorporated into peptide backbones and modified with stimuli-responsive units, development of an amino acid toolkit is promising to address this concern. Therefore, our laboratory has been intensively engaged in designing and discovering stimuli-responsive noncanonical amino acids (ncAAs) to expand the toolkit for manipulating peptide assembly under various biological conditions. Thus far, we have synthesized peptides containing ncAAs 4-aminoproline, 2-nitroimidazole alanine, Se-methionine, sulfated tyrosine, and glycosylated serine, which allow us to develop acid-responsive, redox-responsive, and enzyme-responsive assembly systems. Based on these stimuli-responsive ncAAs, we have established complex self-sorting assembly, self-amplified assembly, and dissipative assembly systems in living cells to optimize the bioactivity of peptides. The resulting in situ assembly systems exhibit morphological adaptability to the biological microenvironment, which contributes to overcoming delivery barriers and improvement of targeting accumulation. Therefore, by utilizing the developed toolkit, we have further created supramolecular PROTACs, supramolecula","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 7","pages":"1081–1093 1081–1093"},"PeriodicalIF":16.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-18Epub Date: 2025-02-27DOI: 10.1021/acs.accounts.5c00024
Li Zhang, Fei-Yu Zhou, Lei Jiao
<p><p>ConspectusPyridine is a crucial heterocyclic compound in organic chemistry. Typically, the pyridine motif behaves as an N-nucleophile and an electron-deficient aromatic ring. Transforming the pyridine ring into an electron-rich system that exhibits reactivity contrary to classical expectations could unveil new opportunities in pyridine chemistry. This Account describes an approach to the umpolung reactivity of the pyridine ring through the formation of an unprecedented <i>N</i>-boryl pyridyl anion (<i>N</i>-BPA) intermediate that enables new catalysis and transformations.In 2017, we discovered that 4-phenylpyridine acts as an efficient catalyst for the borylation of iodo- and bromoarenes using diboron(4) compounds. Mechanistic studies revealed that the <i>in situ</i> formation of an <i>N</i>-BPA intermediate in the pyridine/diboron(4)/methoxide reaction system is a pivotal step in this transformation. Further investigations showed that <i>N</i>-BPA exhibits dual reactivities as both a strong electron donor and a potent nucleophile. This unique reactivity profile has unveiled novel pathways for redox catalysis, pyridine derivatizations, and umpolung transformations.Based on the electron-donor characteristic of the <i>N</i>-boryl pyridyl anion, we have developed a redox catalytic system mediated by a pyridine catalyst. In the pyridine/diboron(4)/base reaction system, the <i>in situ</i> formation of <i>N</i>-BPA followed by single electron transfer (SET) to a substrate with regeneration of the pyridine molecule establishes a redox catalytic cycle. This approach enables the single-electron reduction of a variety of substrates employing 4-phenylpyridine as a catalyst and diboron(4) as the electron source. Upon visible-light excitation, this intermediate transitions into its excited state, exhibiting significantly enhanced reductivity. This enables the establishment of a modular photoredox system consisting of various pyridine/diboron(4)/base combinations that allow for fine-tuning of its redox property. Using this strategy, we performed a series of challenging single-electron reduction reactions, including the single -electron reduction of nonactivated chloro- and fluoroarenes, and Birch reduction of arenes.The nucleophilic character of the <i>N</i>-boryl pyridyl anion was effectively harnessed to facilitate pyridine derivatization and umpolung transformations. By directly quenching the <i>in situ</i>-generated <i>N</i>-BPA with a proton source, we developed a practical approach to <i>N</i>-H-1,4-dihydropyridines (DHPs). Bimolecular nucleophilic substitution reaction between <i>N</i>-BPA and an alkyl bromide produced a 4-alkyl-1,4-DHP, which subsequently releases an alkyl radical under photoredox conditions. This process enabled a catalytic transformation of alkyl bromides into alkyl radicals. Employing 4-trifluoromethylpyridine in this chemistry, the resulting <i>N</i>-BPA intermediate undergoes elimination of fluoride to yield a 4-pyridyldiflu
{"title":"<i>N</i>-Boryl Pyridyl Anion Chemistry.","authors":"Li Zhang, Fei-Yu Zhou, Lei Jiao","doi":"10.1021/acs.accounts.5c00024","DOIUrl":"10.1021/acs.accounts.5c00024","url":null,"abstract":"<p><p>ConspectusPyridine is a crucial heterocyclic compound in organic chemistry. Typically, the pyridine motif behaves as an N-nucleophile and an electron-deficient aromatic ring. Transforming the pyridine ring into an electron-rich system that exhibits reactivity contrary to classical expectations could unveil new opportunities in pyridine chemistry. This Account describes an approach to the umpolung reactivity of the pyridine ring through the formation of an unprecedented <i>N</i>-boryl pyridyl anion (<i>N</i>-BPA) intermediate that enables new catalysis and transformations.In 2017, we discovered that 4-phenylpyridine acts as an efficient catalyst for the borylation of iodo- and bromoarenes using diboron(4) compounds. Mechanistic studies revealed that the <i>in situ</i> formation of an <i>N</i>-BPA intermediate in the pyridine/diboron(4)/methoxide reaction system is a pivotal step in this transformation. Further investigations showed that <i>N</i>-BPA exhibits dual reactivities as both a strong electron donor and a potent nucleophile. This unique reactivity profile has unveiled novel pathways for redox catalysis, pyridine derivatizations, and umpolung transformations.Based on the electron-donor characteristic of the <i>N</i>-boryl pyridyl anion, we have developed a redox catalytic system mediated by a pyridine catalyst. In the pyridine/diboron(4)/base reaction system, the <i>in situ</i> formation of <i>N</i>-BPA followed by single electron transfer (SET) to a substrate with regeneration of the pyridine molecule establishes a redox catalytic cycle. This approach enables the single-electron reduction of a variety of substrates employing 4-phenylpyridine as a catalyst and diboron(4) as the electron source. Upon visible-light excitation, this intermediate transitions into its excited state, exhibiting significantly enhanced reductivity. This enables the establishment of a modular photoredox system consisting of various pyridine/diboron(4)/base combinations that allow for fine-tuning of its redox property. Using this strategy, we performed a series of challenging single-electron reduction reactions, including the single -electron reduction of nonactivated chloro- and fluoroarenes, and Birch reduction of arenes.The nucleophilic character of the <i>N</i>-boryl pyridyl anion was effectively harnessed to facilitate pyridine derivatization and umpolung transformations. By directly quenching the <i>in situ</i>-generated <i>N</i>-BPA with a proton source, we developed a practical approach to <i>N</i>-H-1,4-dihydropyridines (DHPs). Bimolecular nucleophilic substitution reaction between <i>N</i>-BPA and an alkyl bromide produced a 4-alkyl-1,4-DHP, which subsequently releases an alkyl radical under photoredox conditions. This process enabled a catalytic transformation of alkyl bromides into alkyl radicals. Employing 4-trifluoromethylpyridine in this chemistry, the resulting <i>N</i>-BPA intermediate undergoes elimination of fluoride to yield a 4-pyridyldiflu","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1023-1035"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-18Epub Date: 2025-03-06DOI: 10.1021/acs.accounts.5c00014
Rui Zhang, Guangbin Dong
<p><p>ConspectusMethods that can directly modify the skeletons of complex molecules have become increasingly attractive for preparing novel analogues without the need for <i>de novo</i> synthesis in drug discovery processes. Among the various skeletal modification approaches, those targeting unstrained C-C bonds are particularly challenging to realize, owing to the relative inertness of these bonds toward common reagents. Compared to C-H or C-X (X: heteroatom) bonds, the activation of unstrained C-C bonds is often not thermodynamically and/or kinetically favorable. As a result, strategies relying on highly strained substrates or oxidative conditions are generally employed, which inevitably limit the scope and applications of C-C bond activation reactions. Hence, the development of redox-neutral catalytic C-C activation methods remains highly sought after for late-stage skeletal modification of complex bioactive compounds.In this Account, we summarize our recent progress in skeletal modifications through the catalytic activation of relatively unstrained C-C bonds. Enabled by transient or removable directing groups (DGs), the scope of C-C bond activation can be greatly expanded, encompassing a wide range of substrates, including ketones, amides, lactams, and biaryls. Consequently, different types of skeletal modification transformations have been developed. The major topics covered include the following: (1) Skeletal rearrangement and "cut-and-sew" transformations of cyclic ketones: we developed an aminopyridine/Rh-<i>N</i>-heterocyclic carbene (NHC) cooperative catalysis system that specifically targets the α-C-C bond of cyclic ketones. For substrates bearing a β-aryl substitution, the rhodacycle formed after the C-C bond activation can undergo an intramolecular C-H activation, resulting in the skeletal rearrangement from cyclopentanones/cyclohexanones to 1-tetralones/1-indanones. Additionally, the "cut-and-sew" transformations between indanones and ethylene or alkynes have been realized to offer a two-carbon ring expansion. (2) Chain homologation of linear amides and downsizing of lactams: the Rh-NHC activation system can be extended to the linear amides and lactams through preinstalling removable DGs. This approach has provided some new tools for precise amide modifications, including tunable homologation of tertiary amides via a "hook-and-slide" strategy and the downsizing transformation of lactams. (3) "Cut-and-sew" transformations of biphenols: using the preinstalled phosphinite DGs, unstrained 2,2'-biphenols can undergo split cross-coupling with various aryl iodides. When diiodide coupling partners are used, an interesting phenylene insertion into the aryl-aryl bond of biphenols can be achieved, which represents another type of "cut-and-sew" transformation.Collectively, these methods provide a reliable means to manipulate inert molecular scaffolds and offer new bond-disconnecting strategies to access useful structural motifs. The application
{"title":"Skeletal Modification via Activation of Relatively Unstrained C-C Bonds.","authors":"Rui Zhang, Guangbin Dong","doi":"10.1021/acs.accounts.5c00014","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00014","url":null,"abstract":"<p><p>ConspectusMethods that can directly modify the skeletons of complex molecules have become increasingly attractive for preparing novel analogues without the need for <i>de novo</i> synthesis in drug discovery processes. Among the various skeletal modification approaches, those targeting unstrained C-C bonds are particularly challenging to realize, owing to the relative inertness of these bonds toward common reagents. Compared to C-H or C-X (X: heteroatom) bonds, the activation of unstrained C-C bonds is often not thermodynamically and/or kinetically favorable. As a result, strategies relying on highly strained substrates or oxidative conditions are generally employed, which inevitably limit the scope and applications of C-C bond activation reactions. Hence, the development of redox-neutral catalytic C-C activation methods remains highly sought after for late-stage skeletal modification of complex bioactive compounds.In this Account, we summarize our recent progress in skeletal modifications through the catalytic activation of relatively unstrained C-C bonds. Enabled by transient or removable directing groups (DGs), the scope of C-C bond activation can be greatly expanded, encompassing a wide range of substrates, including ketones, amides, lactams, and biaryls. Consequently, different types of skeletal modification transformations have been developed. The major topics covered include the following: (1) Skeletal rearrangement and \"cut-and-sew\" transformations of cyclic ketones: we developed an aminopyridine/Rh-<i>N</i>-heterocyclic carbene (NHC) cooperative catalysis system that specifically targets the α-C-C bond of cyclic ketones. For substrates bearing a β-aryl substitution, the rhodacycle formed after the C-C bond activation can undergo an intramolecular C-H activation, resulting in the skeletal rearrangement from cyclopentanones/cyclohexanones to 1-tetralones/1-indanones. Additionally, the \"cut-and-sew\" transformations between indanones and ethylene or alkynes have been realized to offer a two-carbon ring expansion. (2) Chain homologation of linear amides and downsizing of lactams: the Rh-NHC activation system can be extended to the linear amides and lactams through preinstalling removable DGs. This approach has provided some new tools for precise amide modifications, including tunable homologation of tertiary amides via a \"hook-and-slide\" strategy and the downsizing transformation of lactams. (3) \"Cut-and-sew\" transformations of biphenols: using the preinstalled phosphinite DGs, unstrained 2,2'-biphenols can undergo split cross-coupling with various aryl iodides. When diiodide coupling partners are used, an interesting phenylene insertion into the aryl-aryl bond of biphenols can be achieved, which represents another type of \"cut-and-sew\" transformation.Collectively, these methods provide a reliable means to manipulate inert molecular scaffolds and offer new bond-disconnecting strategies to access useful structural motifs. The application","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 6","pages":"991-1002"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-18Epub Date: 2025-02-26DOI: 10.1021/acs.accounts.4c00854
Hong Lu, Jie Chang, Hao Wei
<p><p>Conspectus<i>N</i>-Heterocycles are essential in pharmaceutical engineering, materials science, and synthetic chemistry. Recently, skeletal editing, which involves making specific point changes to the core of a molecule through single-atom insertion, deletion, or transmutation, has gained attention for its potential to modify complex substrates. In this context, the insertion of nitrogen atoms into carbocycles to form <i>N</i>-heterocycles has emerged as a significant research focus in modern synthetic chemistry owing to its novel synthetic logic. This distinctive retrosynthetic approach enables late-stage modification of molecular skeletons and provides a different pathway for synthesizing multiply substituted <i>N</i>-heterocycles. Nevertheless, nitrogen atom insertion into carbocycles has proven challenging because of the inherent inertness of carbon-based skeletons and difficulty in cleaving C-C bonds. Therefore, selective insertion of nitrogen atoms for skeletal editing remains a challenging and growing field in synthetic chemistry. This Account primarily highlights the contributions of our laboratory to this active field and acknowledges the key contributions from other researchers. It is organized into two sections based on the type of the carbocycle. The first section explores the insertion of nitrogen atoms into cycloalkenes. Recent Co-catalyzed oxidative azidation strategies have enabled nitrogen atom insertion into cyclobutenes, cyclopentenes, and cyclohexenes, facilitating the synthesis of polysubstituted pyridines, which has been conventionally challenging through pyridine cross-coupling. The subsequent section highlights our discovery in the realm of nitrogen atom insertion into arenes. The site-selective skeletal editing of stable arenes is challenging in synthetic chemistry. We developed a method for the intramolecular insertion of nitrogen atoms into the benzene rings of 2-amino biaryls by suppressing the competing C-H insertion process by using a paddlewheel dirhodium catalyst. In addition, to address the challenging site-selective issues in nitrogen atom insertion, we employed arenols as substrates, which could act as selective controlling elements in site-selective skeletal editing. We reported a Cu-catalyzed nitrogen atom insertion into arenols, which proceeds through a dearomative azidation/aryl migration process, enabling the site-selective incorporation of nitrogen atoms into arenes. Inspired by this result, we recently extended the reaction model by using a Fe-catalyst to facilitate the ring contraction of the nitrogen-inserted product, achieving the carbon-to-nitrogen transmutation of arenols. Various complex polyaromatic arenols could effectively undergo the desired atom's transmutation, presenting considerable potential for various applications in materials chemistry. In this Account, we present an overview of our achievements in nitrogen atom insertion reactions, with a focus on the reaction scopes, mechanistic
{"title":"Transition Metal-Catalyzed Nitrogen Atom Insertion into Carbocycles.","authors":"Hong Lu, Jie Chang, Hao Wei","doi":"10.1021/acs.accounts.4c00854","DOIUrl":"10.1021/acs.accounts.4c00854","url":null,"abstract":"<p><p>Conspectus<i>N</i>-Heterocycles are essential in pharmaceutical engineering, materials science, and synthetic chemistry. Recently, skeletal editing, which involves making specific point changes to the core of a molecule through single-atom insertion, deletion, or transmutation, has gained attention for its potential to modify complex substrates. In this context, the insertion of nitrogen atoms into carbocycles to form <i>N</i>-heterocycles has emerged as a significant research focus in modern synthetic chemistry owing to its novel synthetic logic. This distinctive retrosynthetic approach enables late-stage modification of molecular skeletons and provides a different pathway for synthesizing multiply substituted <i>N</i>-heterocycles. Nevertheless, nitrogen atom insertion into carbocycles has proven challenging because of the inherent inertness of carbon-based skeletons and difficulty in cleaving C-C bonds. Therefore, selective insertion of nitrogen atoms for skeletal editing remains a challenging and growing field in synthetic chemistry. This Account primarily highlights the contributions of our laboratory to this active field and acknowledges the key contributions from other researchers. It is organized into two sections based on the type of the carbocycle. The first section explores the insertion of nitrogen atoms into cycloalkenes. Recent Co-catalyzed oxidative azidation strategies have enabled nitrogen atom insertion into cyclobutenes, cyclopentenes, and cyclohexenes, facilitating the synthesis of polysubstituted pyridines, which has been conventionally challenging through pyridine cross-coupling. The subsequent section highlights our discovery in the realm of nitrogen atom insertion into arenes. The site-selective skeletal editing of stable arenes is challenging in synthetic chemistry. We developed a method for the intramolecular insertion of nitrogen atoms into the benzene rings of 2-amino biaryls by suppressing the competing C-H insertion process by using a paddlewheel dirhodium catalyst. In addition, to address the challenging site-selective issues in nitrogen atom insertion, we employed arenols as substrates, which could act as selective controlling elements in site-selective skeletal editing. We reported a Cu-catalyzed nitrogen atom insertion into arenols, which proceeds through a dearomative azidation/aryl migration process, enabling the site-selective incorporation of nitrogen atoms into arenes. Inspired by this result, we recently extended the reaction model by using a Fe-catalyst to facilitate the ring contraction of the nitrogen-inserted product, achieving the carbon-to-nitrogen transmutation of arenols. Various complex polyaromatic arenols could effectively undergo the desired atom's transmutation, presenting considerable potential for various applications in materials chemistry. In this Account, we present an overview of our achievements in nitrogen atom insertion reactions, with a focus on the reaction scopes, mechanistic ","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"933-946"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-18Epub Date: 2025-03-05DOI: 10.1021/acs.accounts.5c00011
Kenneth A Jacobson
<p><p>The author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating purinergic signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions for therapeutic intervention. Purinergic signaling encompasses four adenosine receptors, eight P2Y receptors that respond to various extracellular nucleotides, and trimeric P2X receptors that respond mainly to ATP. Each organ and tissue in the body expresses some combination of this family of cell-surface receptors, along with the enzymes and transporters that form, degrade, and process the native nucleoside and nucleotide agonists. The purinergic signaling system responds to physiological stress to an organ, for example by increasing the energy supply or decreasing the energy demand. The receptors are widespread on immune cells, such that P2Y and P2X receptor activation boosts the immune response when and where it is needed, for example to repel infection. In contrast, the adenosine receptors, which are activated later in the process─as stress-elevated ATP is hydrolyzed locally to adenosine by ectonucleotidases─tend to put the brakes on inflammation and can be used to correct an imbalance in pro- versus anti-inflammatory signals, such as in chronic pain. Hypoxia activates the immunosuppressive extracellular adenosine-A<sub>2A</sub> adenosine receptor axis, as originally formulated by Sitkovsky, which suppresses the immune response in the tumor microenvironment to make a cancer more aggressive. Conversely, the anti-inflammatory effects of adenosine receptor agonists have numerous therapeutic applications. Modulators of P2Y receptors, which respond to extracellular nucleotides, also show promise for treating chronic pain, metabolic disorders, and inflammation. Thus, control of this signaling system can be harnessed for treating a wide range of conditions, from cancer and neurodegeneration to autoimmune inflammatory diseases to ischemia of the brain or heart. The author's receiving the American Chemical Society's top award for medicinal chemistry in 2023 provides an opportunity to summarize these developments from their origins in empirical probing of receptor-ligand structure-activity relationship (SAR) to the current structure-based approaches, including conformational control of selectivity toward purinergic signaling. The work on each target receptor began either before or soon after it was cloned, and the initial focus was an academic exercise to use organic chemistry to develop a SAR for each target. The Jacobson lab has introduced chemical probes for 17 of the purinergic receptors as well as for associated regulators. Furthermore, surprisingly, some of the conformationally constrained nucleoside analogues can be designed to inhibit non-purinergic targets selectively, such as opioid and serotonin receptors and monoamine tr
{"title":"E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling.","authors":"Kenneth A Jacobson","doi":"10.1021/acs.accounts.5c00011","DOIUrl":"10.1021/acs.accounts.5c00011","url":null,"abstract":"<p><p>The author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating purinergic signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions for therapeutic intervention. Purinergic signaling encompasses four adenosine receptors, eight P2Y receptors that respond to various extracellular nucleotides, and trimeric P2X receptors that respond mainly to ATP. Each organ and tissue in the body expresses some combination of this family of cell-surface receptors, along with the enzymes and transporters that form, degrade, and process the native nucleoside and nucleotide agonists. The purinergic signaling system responds to physiological stress to an organ, for example by increasing the energy supply or decreasing the energy demand. The receptors are widespread on immune cells, such that P2Y and P2X receptor activation boosts the immune response when and where it is needed, for example to repel infection. In contrast, the adenosine receptors, which are activated later in the process─as stress-elevated ATP is hydrolyzed locally to adenosine by ectonucleotidases─tend to put the brakes on inflammation and can be used to correct an imbalance in pro- versus anti-inflammatory signals, such as in chronic pain. Hypoxia activates the immunosuppressive extracellular adenosine-A<sub>2A</sub> adenosine receptor axis, as originally formulated by Sitkovsky, which suppresses the immune response in the tumor microenvironment to make a cancer more aggressive. Conversely, the anti-inflammatory effects of adenosine receptor agonists have numerous therapeutic applications. Modulators of P2Y receptors, which respond to extracellular nucleotides, also show promise for treating chronic pain, metabolic disorders, and inflammation. Thus, control of this signaling system can be harnessed for treating a wide range of conditions, from cancer and neurodegeneration to autoimmune inflammatory diseases to ischemia of the brain or heart. The author's receiving the American Chemical Society's top award for medicinal chemistry in 2023 provides an opportunity to summarize these developments from their origins in empirical probing of receptor-ligand structure-activity relationship (SAR) to the current structure-based approaches, including conformational control of selectivity toward purinergic signaling. The work on each target receptor began either before or soon after it was cloned, and the initial focus was an academic exercise to use organic chemistry to develop a SAR for each target. The Jacobson lab has introduced chemical probes for 17 of the purinergic receptors as well as for associated regulators. Furthermore, surprisingly, some of the conformationally constrained nucleoside analogues can be designed to inhibit non-purinergic targets selectively, such as opioid and serotonin receptors and monoamine tr","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"958-970"},"PeriodicalIF":16.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：