Accounts of Chemical Research最新文献

{"title":"Explaining Kinetic Isotope Effects in Proton-Coupled Electron Transfer Reactions","authors":"Sharon Hammes-Schiffer","doi":"10.1021/acs.accounts.5c00119","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00119","url":null,"abstract":"Proton-coupled electron transfer (PCET) is essential for a wide range of chemical and biological processes. Understanding the mechanism of PCET reactions is important for controlling and tuning these processes. The kinetic isotope effect (KIE), defined as the ratio of the rate constants for hydrogen and deuterium transfer, is used to probe PCET mechanisms experimentally but is often challenging to interpret. Herein, a theoretical framework is described for interpreting KIEs of concerted PCET reactions. The first step is to classify the reaction in terms of vibronic and electron–proton nonadiabaticities, which reflect the relative time scales of the electrons, protons, and environment. The second step is to select the appropriate rate constant expression based on this classification. The third step is to compute the input quantities with computational methods.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"8 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782892","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}

{"title":"Inorganic Nanobiomaterials Boost Tumor Immunotherapy: Strategies and Applications.","authors":"Qi Meng, Binbin Ding, Ping'an Ma, Jun Lin","doi":"10.1021/acs.accounts.4c00843","DOIUrl":"https://doi.org/10.1021/acs.accounts.4c00843","url":null,"abstract":"<p><p>ConspectusTumor immunotherapy, as a new antitumor method to fight cancer by activating or enhancing the body's own immune system, has been extensively studied and applied in clinical practice. However, as an extremely complex system, tumor heterogeneity and complex immunosuppressive tumor microenvironment (TME) lead to poor immune response rate or secondary drug resistance. The advent of nanotechnology has ushered in a new era for immunotherapy. In particular, inorganic nanomaterials, with their unique physicochemical properties and excellent biocompatibility, are becoming an important tool for enhancing immunotherapy. Inorganic nanomaterials can be used as carriers for immune agents, improving drug delivery efficiency and thereby reducing systemic immunotoxicity and enhancing immune responses. Inorganic nanomaterials also trigger tumor immunogenic cell death (ICD), stimulate antitumor immune responses, and alleviate immunosuppressive TME by increasing oxygen levels, modulating metabolic pathways, and altering the secretion of immunosuppressive cytokines. The synergistic integration of inorganic nanomaterials with immunotherapy adeptly navigates around the constraints of conventional treatments, reducing side effects while concurrently augmenting therapeutic efficacy. In this review, we summarize our recent efforts in the design and synthesis of inorganic nanobiomaterials to enhance the efficacy of tumor immunotherapy. These nanomaterials achieve the desired immune efficacy mainly through four strategies, including inducing ICD, developing tumor nanovaccines, activating pyroptosis, and regulating tumor metabolism, providing beneficial implications for tumor immunotherapy. For one thing, due to the deficiency of ICD effect in single therapy, we mainly developed nanocatalysts that integrate multiple therapeutic functions to play a catalytic role in TME, converting tumor substances or metabolites into therapeutic products in situ, and further enhancing ICD. For another, in order to solve the problems of low antigen loading and therapeutic efficiency of existing adjuvants, several novel multifunctional nanoadjuvants were prepared, which combine high antigen loading and multimode therapeutic function in one, and achieve efficient immune activation. Moreover, to attain strong inflammatory responses and immunogenicity, we engineer pyroptosis adjuvants that selectively induce tumor cell pyroptosis by enhancing intracellular oxidative stress or ion overload. Finally, to reverse the immunosuppressive microenvironment, we developed nanoplatforms that target tumor metabolism, altering the levels of nutrients and metabolites in tumor such as glucose, lactic acid, citric acid, and tryptophan to effectively alter the TME, thereby activating and enhancing the body's immune response. The implementation of these strategies not only improves the therapeutic effect but also reduces the side effects and provides valuable insights and references for the developm","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778533","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}

{"title":"Inorganic Nanobiomaterials Boost Tumor Immunotherapy: Strategies and Applications","authors":"Qi Meng, Binbin Ding*, Ping’an Ma* and Jun Lin*, ","doi":"10.1021/acs.accounts.4c0084310.1021/acs.accounts.4c00843","DOIUrl":"https://doi.org/10.1021/acs.accounts.4c00843https://doi.org/10.1021/acs.accounts.4c00843","url":null,"abstract":"<p >Tumor immunotherapy, as a new antitumor method to fight cancer by activating or enhancing the body’s own immune system, has been extensively studied and applied in clinical practice. However, as an extremely complex system, tumor heterogeneity and complex immunosuppressive tumor microenvironment (TME) lead to poor immune response rate or secondary drug resistance. The advent of nanotechnology has ushered in a new era for immunotherapy. In particular, inorganic nanomaterials, with their unique physicochemical properties and excellent biocompatibility, are becoming an important tool for enhancing immunotherapy. Inorganic nanomaterials can be used as carriers for immune agents, improving drug delivery efficiency and thereby reducing systemic immunotoxicity and enhancing immune responses. Inorganic nanomaterials also trigger tumor immunogenic cell death (ICD), stimulate antitumor immune responses, and alleviate immunosuppressive TME by increasing oxygen levels, modulating metabolic pathways, and altering the secretion of immunosuppressive cytokines. The synergistic integration of inorganic nanomaterials with immunotherapy adeptly navigates around the constraints of conventional treatments, reducing side effects while concurrently augmenting therapeutic efficacy. In this review, we summarize our recent efforts in the design and synthesis of inorganic nanobiomaterials to enhance the efficacy of tumor immunotherapy. These nanomaterials achieve the desired immune efficacy mainly through four strategies, including inducing ICD, developing tumor nanovaccines, activating pyroptosis, and regulating tumor metabolism, providing beneficial implications for tumor immunotherapy. For one thing, due to the deficiency of ICD effect in single therapy, we mainly developed nanocatalysts that integrate multiple therapeutic functions to play a catalytic role in TME, converting tumor substances or metabolites into therapeutic products in situ, and further enhancing ICD. For another, in order to solve the problems of low antigen loading and therapeutic efficiency of existing adjuvants, several novel multifunctional nanoadjuvants were prepared, which combine high antigen loading and multimode therapeutic function in one, and achieve efficient immune activation. Moreover, to attain strong inflammatory responses and immunogenicity, we engineer pyroptosis adjuvants that selectively induce tumor cell pyroptosis by enhancing intracellular oxidative stress or ion overload. Finally, to reverse the immunosuppressive microenvironment, we developed nanoplatforms that target tumor metabolism, altering the levels of nutrients and metabolites in tumor such as glucose, lactic acid, citric acid, and tryptophan to effectively alter the TME, thereby activating and enhancing the body’s immune response. The implementation of these strategies not only improves the therapeutic effect but also reduces the side effects and provides valuable insights and references for the development of novel","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1210–1223 1210–1223"},"PeriodicalIF":16.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828122","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}

{"title":"Total Synthesis of Polycyclic Natural Products via Photoenolization/Diels-Alder Reaction.","authors":"Baochao Yang, Min Hou, Shuanhu Gao","doi":"10.1021/acs.accounts.5c00084","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00084","url":null,"abstract":"<p><p>ConspectusPolycyclic ring systems represent the most common structural features of drug molecules and natural products. Chemical synthesis of complex polycyclic molecules with multiple stereogenic centers, especially quaternary carbon stereocenters, has been a significant challenge in the field of total synthesis. Due to the low reactivities of the substrates and congested chemical environments, the efficient establishment of polycyclic rings and enantioselective construction of quaternary carbon stereocenters are still ongoing challenges. In our laboratory, we are devoted to developing new methodologies and strategies for the total syntheses of bioactive polycyclic natural products and the exploration of their biological potentials. The photoenolization/Diels-Alder (PEDA) reaction has been recognized as a powerful strategy to increase synthetic efficiency and address the aforementioned issues. Over the past several years, our group systematically reinvestigated this reaction in terms of its reactivity and stereoselectivity and developed a unique dinuclear metal-promoted reaction process for constructing fused or spiro polycyclic rings bearing quaternary carbon stereocenters. During the course of this investigation, we have come to realize how to rationally design the synthetic route based on the PEDA reaction and successfully implement the synthetic projects.In this Account, we summarize our endeavors and journeys in the development and application of the PEDA reaction to the total synthesis of topologically complex natural products in order to draw attention to its broad utility and encourage further uptake. In the first part, we provide the details on the investigation of the PEDA reaction to address the issues of reactivity, diastereoselectivity, and enantioselectivity. An enantioselective PEDA reaction involving Ti(O<i>i</i>-Pr)<sub>4</sub> and TADDOL-type ligands was developed. This reaction enables the sterically bulky dienophiles to interact with the transient photoenolized hydroxy-<i>o</i>-quinodimethanes, delivering a wide range of polycyclic rings with single or vicinal quaternary carbon stereocenters in good yields with excellent enantioselectivities. In the second part, we showcase the synthetic potential of PEDA reaction in total synthesis of natural products. The fused tricyclic ring systems, bearing <i>gem</i>-dimethyl groups or quaternary carbon stereocenters located at the ring junction, were efficiently constructed by Ti(O<i>i</i>-Pr)<sub>4</sub>-promoted PEDA reactions, which enabled the syntheses of three different types of natural products, including aromatic polyketides (anthrabenzoxocinones, fasamycins/naphthacemycins, and benastatins), meroterpenoid (oncocalyxone B), and halenaquinones (xestoquinone, adociaquinones A and B). To access structurally more complex triterpenoids, namely, perovskones and hydrangenones, the asymmetric PEDA reaction was developed to build a tricyclic ring along with three contiguous quatern","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762483","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}

{"title":"Skeletal Editing of Polymer Backbones and Its Impact Across the Polymer Lifecycle.","authors":"Sydney E Towell, Mark J Jareczek, Lauren S Cooke, Daniel R Godfrey, Aleksandr V Zhukhovitskiy","doi":"10.1021/acs.accounts.5c00054","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00054","url":null,"abstract":"<p><p>ConspectusIn the last five years, interest in the precise modification of molecular cores─termed skeletal editing─has rapidly expanded in the Chemistry community. Beyond the intrinsic value of these transformations, skeletal editing also has value in the attention it brings to under-explored chemical challenges, whose solutions could transform the practice of Chemistry at large. In few contexts does this perspective ring as true as in the realm of polymers. Inspired by the revolutionary power of biologically derived machinery called CRISPR-Cas9 to edit nucleic acid polymers and, consequently, the genetic meaning encoded in them, we envisioned that skeletal editing of synthetic polymer backbones may also enable control over the structure and \"meaning\"─i.e., properties and function─of plastics. However, the idea of editing polymer backbones brings about numerous fundamental chemical questions that must be answered to make the vision a reality: for instance, how to constructively activate carbon-carbon and carbon-heteroatom bonds that make up typical polymer backbones and how to do so in a site-selective manner? While many fundamental questions have begun to be answered by the small molecule community, they are yet to be applied to the realm of polymers, and such adaptation often begets new scientific challenges. Moreover, as we begin to tackle these questions, we must always consider how advances in skeletal editing of polymer backbones impact the broader contexts of applications and sustainability of plastics.In this Account, we summarize our efforts to advance the skeletal editing of polymer backbones, focusing on how such methods can affect each stage of the polymer lifecycle: (1) provide an entry to previously challenging-to-access functional polymers or to existing ones but from new feedstocks, (2) evolve one type of polymer into another with associated changes in material properties, and (3) enable the breakdown of otherwise intractable polymer backbones. Along the way, we describe our rationale behind the selection and development of reactions utilized for skeletal editing. We explain how small molecule reactions often need to be adapted to suit polymeric substrates and the methodology optimizations we needed to do to accomplish our edits. We also discuss the considerations involved in the selection or design of polymeric substrates for editing with an eye toward what edits can add to polymer function and how to advance the field. We conclude with an outlook on outstanding challenges that we aim to address in future work establishing areas for future exploration within each of our topic areas.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770682","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}

{"title":"Total Synthesis of Polycyclic Natural Products via Photoenolization/Diels–Alder Reaction","authors":"Baochao Yang,&nbsp;Min Hou and Shuanhu Gao*,&nbsp;","doi":"10.1021/acs.accounts.5c0008410.1021/acs.accounts.5c00084","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00084https://doi.org/10.1021/acs.accounts.5c00084","url":null,"abstract":"&lt;p &gt;Polycyclic ring systems represent the most common structural features of drug molecules and natural products. Chemical synthesis of complex polycyclic molecules with multiple stereogenic centers, especially quaternary carbon stereocenters, has been a significant challenge in the field of total synthesis. Due to the low reactivities of the substrates and congested chemical environments, the efficient establishment of polycyclic rings and enantioselective construction of quaternary carbon stereocenters are still ongoing challenges. In our laboratory, we are devoted to developing new methodologies and strategies for the total syntheses of bioactive polycyclic natural products and the exploration of their biological potentials. The photoenolization/Diels–Alder (PEDA) reaction has been recognized as a powerful strategy to increase synthetic efficiency and address the aforementioned issues. Over the past several years, our group systematically reinvestigated this reaction in terms of its reactivity and stereoselectivity and developed a unique dinuclear metal-promoted reaction process for constructing fused or spiro polycyclic rings bearing quaternary carbon stereocenters. During the course of this investigation, we have come to realize how to rationally design the synthetic route based on the PEDA reaction and successfully implement the synthetic projects.&lt;/p&gt;&lt;p &gt;In this Account, we summarize our endeavors and journeys in the development and application of the PEDA reaction to the total synthesis of topologically complex natural products in order to draw attention to its broad utility and encourage further uptake. In the first part, we provide the details on the investigation of the PEDA reaction to address the issues of reactivity, diastereoselectivity, and enantioselectivity. An enantioselective PEDA reaction involving Ti(O&lt;i&gt;i&lt;/i&gt;-Pr)&lt;sub&gt;4&lt;/sub&gt; and TADDOL-type ligands was developed. This reaction enables the sterically bulky dienophiles to interact with the transient photoenolized hydroxy-&lt;i&gt;o&lt;/i&gt;-quinodimethanes, delivering a wide range of polycyclic rings with single or vicinal quaternary carbon stereocenters in good yields with excellent enantioselectivities. In the second part, we showcase the synthetic potential of PEDA reaction in total synthesis of natural products. The fused tricyclic ring systems, bearing &lt;i&gt;gem&lt;/i&gt;-dimethyl groups or quaternary carbon stereocenters located at the ring junction, were efficiently constructed by Ti(O&lt;i&gt;i&lt;/i&gt;-Pr)&lt;sub&gt;4&lt;/sub&gt;-promoted PEDA reactions, which enabled the syntheses of three different types of natural products, including aromatic polyketides (anthrabenzoxocinones, fasamycins/naphthacemycins, and benastatins), meroterpenoid (oncocalyxone B), and halenaquinones (xestoquinone, adociaquinones A and B). To access structurally more complex triterpenoids, namely, perovskones and hydrangenones, the asymmetric PEDA reaction was developed to build a tricyclic ring along with three contiguous quaternary","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1308–1322 1308–1322"},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827857","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}

{"title":"Skeletal Editing of Polymer Backbones and Its Impact Across the Polymer Lifecycle","authors":"Sydney E. Towell,&nbsp;Mark J. Jareczek,&nbsp;Lauren S. Cooke,&nbsp;Daniel R. Godfrey and Aleksandr V. Zhukhovitskiy*,&nbsp;","doi":"10.1021/acs.accounts.5c0005410.1021/acs.accounts.5c00054","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00054https://doi.org/10.1021/acs.accounts.5c00054","url":null,"abstract":"<p >In the last five years, interest in the precise modification of molecular cores─termed skeletal editing─has rapidly expanded in the Chemistry community. Beyond the intrinsic value of these transformations, skeletal editing also has value in the attention it brings to under-explored chemical challenges, whose solutions could transform the practice of Chemistry at large. In few contexts does this perspective ring as true as in the realm of polymers. Inspired by the revolutionary power of biologically derived machinery called CRISPR-Cas9 to edit nucleic acid polymers and, consequently, the genetic meaning encoded in them, we envisioned that skeletal editing of synthetic polymer backbones may also enable control over the structure and “meaning”─i.e., properties and function─of plastics. However, the idea of editing polymer backbones brings about numerous fundamental chemical questions that must be answered to make the vision a reality: for instance, how to constructively activate carbon–carbon and carbon–heteroatom bonds that make up typical polymer backbones and how to do so in a site-selective manner? While many fundamental questions have begun to be answered by the small molecule community, they are yet to be applied to the realm of polymers, and such adaptation often begets new scientific challenges. Moreover, as we begin to tackle these questions, we must always consider how advances in skeletal editing of polymer backbones impact the broader contexts of applications and sustainability of plastics.</p><p >In this Account, we summarize our efforts to advance the skeletal editing of polymer backbones, focusing on how such methods can affect each stage of the polymer lifecycle: (1) provide an entry to previously challenging-to-access functional polymers or to existing ones but from new feedstocks, (2) evolve one type of polymer into another with associated changes in material properties, and (3) enable the breakdown of otherwise intractable polymer backbones. Along the way, we describe our rationale behind the selection and development of reactions utilized for skeletal editing. We explain how small molecule reactions often need to be adapted to suit polymeric substrates and the methodology optimizations we needed to do to accomplish our edits. We also discuss the considerations involved in the selection or design of polymeric substrates for editing with an eye toward what edits can add to polymer function and how to advance the field. We conclude with an outlook on outstanding challenges that we aim to address in future work establishing areas for future exploration within each of our topic areas.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1275–1283 1275–1283"},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827757","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}

{"title":"Innovative Chemical Strategies for Advanced CRISPR Modulation","authors":"Xingyu Liu,&nbsp;Enyi Zhou,&nbsp;Qianqian Qi,&nbsp;Wei Xiong,&nbsp;Tian Tian* and Xiang Zhou*,&nbsp;","doi":"10.1021/acs.accounts.5c0005210.1021/acs.accounts.5c00052","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00052https://doi.org/10.1021/acs.accounts.5c00052","url":null,"abstract":"&lt;p &gt;Over the past decade, RNA-guided gene editing technologies, particularly those derived from CRISPR systems, have revolutionized life sciences and opened unprecedented opportunities for therapeutic innovation. Despite their transformative potential, achieving precise control over the activity and specificity of these molecular tools remains a formidable challenge, requiring advanced and innovative regulatory strategies. We and others have developed new approaches that integrate chemical ingenuity with bioorthogonal techniques to achieve remarkable precision in CRISPR regulation. One key innovation lies in the chemical modulation of guide RNA (gRNA), significantly expanding the CRISPR toolkit. Strategies such as CRISPR-ON and CRISPR-OFF switches rely on selective chemical masking and demasking of gRNA. These approaches use either bulky chemical groups to preemptively mask RNA or minor, less obstructive groups to fine-tune its function, followed by bioorthogonal reactions to restore or suppress activity. These methodologies have proven to be pivotal for controlled gene editing and expression, addressing the challenges of precision, reversibility, and dynamic regulation.&lt;/p&gt;&lt;p &gt;Parallel to these advances, the development of mesoporous metal–organic frameworks (MOFs) has emerged as a promising solution for RNA deprotection and activation. By serving as catalytic tools, MOFs enhance the versatility and efficiency of CRISPR systems, pushing their applications beyond the conventional boundaries. In addition, the synthesis of novel small molecules for regulating CRISPR-Cas9 activity marks a critical milestone in the evolution of gene therapy protocols. Innovative RNA structural control strategies have also emerged, particularly through the engineering of G-quadruplex (G4) motifs and G–G mismatches. These methods exploit the structural propensities of engineered gRNAs, employing small-molecule ligands to induce specific conformational changes that modulate the CRISPR activity. Whether stabilizing G4 formation or promoting G–G mismatches, these strategies demonstrate the precision and sophistication required for the molecular-level control of gene editing.&lt;/p&gt;&lt;p &gt;Further enhancing these innovations, techniques like host–guest chemistry and conditional diacylation cross-linking have been developed to directly alter gRNA structure and function. These approaches provide nuanced, reversible, and safe control over CRISPR systems, advancing both the precision and reliability of gene editing technologies. In conclusion, this body of work highlights the convergence of chemistry, materials science, and molecular biology to create integrative solutions for gene editing. By combination of bioorthogonal chemistry, RNA engineering, and advanced materials, these advancements offer unprecedented accuracy and control for both fundamental research and therapeutic applications. These innovations not only advance genetic research but also contribute to developing safer a","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1262–1274 1262–1274"},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828116","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}

{"title":"Aromatic Metamorphosis: Skeletal Editing of Aromatic Rings","authors":"Hideki Yorimitsu*,&nbsp;","doi":"10.1021/acs.accounts.5c0009110.1021/acs.accounts.5c00091","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00091https://doi.org/10.1021/acs.accounts.5c00091","url":null,"abstract":"&lt;p &gt;Aromatic rings are fundamental structural motifs found in natural products, synthetic intermediates, pharmaceuticals, agrochemicals, and functional materials. While transformations at the periphery of these rings are well-established, modifying their core frameworks has remained an underexplored frontier. Our group has pioneered the concept, termed “aromatic metamorphosis”, enabling skeletal transformations of aromatic rings by replacing an endocyclic atom with a different atom or inserting an atom into aromatic rings, which leads to novel synthetic strategies and diverse molecular architectures.&lt;/p&gt;&lt;p &gt;The concept of aromatic metamorphosis was first demonstrated in the stepwise conversion of dibenzothiophenes and dibenzofurans into triphenylenes. These transformations, facilitated by palladium and nickel catalysts, involve the strategic activation of robust C–S and C–O bonds as the key steps. Next, the approach was extended to the two-step conversions of dibenzothiophenes into carbazoles, dibenzophospholes, fluorenes, etc., which involve oxidation into the corresponding sulfones and subsequent sequential inter- and intramolecular nucleophilic aromatic substitution reactions. These new synthetic routes have provided efficient access to optoelectronic materials. Especially, the S&lt;sub&gt;N&lt;/sub&gt;Ar-based aromatic metamorphosis facilitated the construction of a heterohelicene library with systematic variation in endocyclic atoms. This strategy has revolutionized the way molecular libraries are constructed and enables the rapid discovery of functional molecules.&lt;/p&gt;&lt;p &gt;In addition to the endocyclic substitutions, ring-expanding aromatic metamorphosis through atom insertion has also been explored. We developed nickel-catalyzed boron insertion into benzofurans, generating benzoxaborins, which are important scaffolds for medicinal chemistry. This novel catalytic transformation has been successfully scaled to industrial synthesis by companies, which demonstrates the practical utility of aromatic metamorphosis. Furthermore, manganese-catalyzed and lithium–metal-promoted methodologies have expanded the ranges of heteroatoms inserted and aromatic frameworks cleaved, providing methods to access heterocycles with a diversity in element compositions.&lt;/p&gt;&lt;p &gt;Reductive dilithiation of thiophenes efficiently yields 1,4-dilithiobutadienes, which react with a variety of electrophiles to produce a series of nonbiogenic heteroles, such as boroles, phospholes, and siloles. In principle, this method should allow the sulfur atom in readily available thiophenes to be replaced with any atom and is therefore considered an ideal example of aromatic metamorphosis in terms of rapid construction of diverse chemical spaces with a variety of elements.&lt;/p&gt;&lt;p &gt;Aromatic metamorphosis proposes many new synthons and retrosynthetic disconnections that defy the conventional wisdom of organic synthesis. By making full use of metamorphosing the aromatic skeleton, a library with skeletal ","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 8","pages":"1323–1334 1323–1334"},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827756","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}

{"title":"Innovative Chemical Strategies for Advanced CRISPR Modulation.","authors":"Xingyu Liu, Enyi Zhou, Qianqian Qi, Wei Xiong, Tian Tian, Xiang Zhou","doi":"10.1021/acs.accounts.5c00052","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00052","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusOver the past decade, RNA-guided gene editing technologies, particularly those derived from CRISPR systems, have revolutionized life sciences and opened unprecedented opportunities for therapeutic innovation. Despite their transformative potential, achieving precise control over the activity and specificity of these molecular tools remains a formidable challenge, requiring advanced and innovative regulatory strategies. We and others have developed new approaches that integrate chemical ingenuity with bioorthogonal techniques to achieve remarkable precision in CRISPR regulation. One key innovation lies in the chemical modulation of guide RNA (gRNA), significantly expanding the CRISPR toolkit. Strategies such as CRISPR-ON and CRISPR-OFF switches rely on selective chemical masking and demasking of gRNA. These approaches use either bulky chemical groups to preemptively mask RNA or minor, less obstructive groups to fine-tune its function, followed by bioorthogonal reactions to restore or suppress activity. These methodologies have proven to be pivotal for controlled gene editing and expression, addressing the challenges of precision, reversibility, and dynamic regulation.Parallel to these advances, the development of mesoporous metal-organic frameworks (MOFs) has emerged as a promising solution for RNA deprotection and activation. By serving as catalytic tools, MOFs enhance the versatility and efficiency of CRISPR systems, pushing their applications beyond the conventional boundaries. In addition, the synthesis of novel small molecules for regulating CRISPR-Cas9 activity marks a critical milestone in the evolution of gene therapy protocols. Innovative RNA structural control strategies have also emerged, particularly through the engineering of G-quadruplex (G4) motifs and G-G mismatches. These methods exploit the structural propensities of engineered gRNAs, employing small-molecule ligands to induce specific conformational changes that modulate the CRISPR activity. Whether stabilizing G4 formation or promoting G-G mismatches, these strategies demonstrate the precision and sophistication required for the molecular-level control of gene editing.Further enhancing these innovations, techniques like host-guest chemistry and conditional diacylation cross-linking have been developed to directly alter gRNA structure and function. These approaches provide nuanced, reversible, and safe control over CRISPR systems, advancing both the precision and reliability of gene editing technologies. In conclusion, this body of work highlights the convergence of chemistry, materials science, and molecular biology to create integrative solutions for gene editing. By combination of bioorthogonal chemistry, RNA engineering, and advanced materials, these advancements offer unprecedented accuracy and control for both fundamental research and therapeutic applications. These innovations not only advance genetic research but also contribute to developing safer and mo","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770681","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}