Accounts of Chemical Research最新文献

{"title":"","authors":"Rahul Giri, Anthony J. Fernandes and Dmitry Katayev*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 13","pages":"962–968 XXX-XXX"},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.accounts.5c00239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516728","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}

{"title":"","authors":"Susannah E. Huth, Elizabeth A. Stone* and Scott J. Miller*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 13","pages":"962–968 XXX-XXX"},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.accounts.5c00247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516735","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}

{"title":"Primary Amine-Based Photoclick Chemistry: From Concept to Diverse Applications in Chemical Biology and Medicinal Chemistry.","authors":"Hao Hu, Hui-Jun Nie, Xiao-Hua Chen","doi":"10.1021/acs.accounts.5c00158","DOIUrl":"10.1021/acs.accounts.5c00158","url":null,"abstract":"<p><p>ConspectusClick chemistry has significantly impacted many fields. The emergence of photoclick chemistry, which harnesses light-driven processes under mild conditions, has introduced distinct advantages, including precise spatiotemporal control, high selectivity, and elimination of toxic metal catalysts and reagents. These features make photoclick chemistry a highly valuable tool in various fields. Although many exciting applications have been found, the development of photoclick methodologies remains limited, and photoclick chemistry is still in its early stage. Thus, the development of novel and versatile systems is crucial for advancing a wide range of applications and fully realizing their potential.In this Account, we aim to highlight the concept of a novel photoclick chemistry, light-induced Primary Amine and <i>o</i>-Nitrobenzyl Alcohol Cyclization (PANAC), to broaden the potential and applications of photoclick chemistry. Inspired by the abundance and versatility of primary amines in synthetic chemistry, biological systems, and materials science, we introduced the primary amine as a direct and general photoclick handle, while the <i>o</i>-nitrobenzyl alcohol (<i>o</i>-NBA) structure was designed as a molecular plugin to provide easily accessible and modular reactants for the PANAC photoclick reaction. With intrinsic features such as temporal control, reliable chemoselectivity, high efficiency, readily accessible reactants, biocompatibility, operational simplicity, and mild conditions, the developed PANAC photoclick reaction aligns with the core criteria of photoclick chemistry. By leveraging the advantages of PANAC photoclick chemistry and designing various conjugation strategies, we have successfully applied it in various applications, enabling modular synthesis and bioconjugation, including modular functionalization of bioactive small molecules, lysine-specific unprotected peptide cyclization and labeling of native proteins both <i>in vitro</i> and in live cells, and temporal profiling of endogenous kinases and organelle-targeted labeling in living systems. Moreover, by harnessing widespread primary amines and the versatility of PANAC photoclick chemistry, we developed a direct-to-biology platform for proteolysis-targeting chimera (PROTAC) library assembly, accelerating PROTAC degrader discovery, and created structurally diverse DNA-encoded libraries for high-throughput screening and identification of novel bioactive compounds. Furthermore, based on primary-amine-based modular synthesis, a general platform for the efficient and modular assembly of ligand-oligonucleotide conjugations via PANAC photoclick chemistry enables rapid access to therapeutic oligonucleotides. More importantly, PANAC photoclick chemistry enables temporally controlled proteome-wide profiling of biomacromolecule interactions and dynamics through endogenous lysine bioconjugation within complex biological environments. This is exemplified by the spatiotemporal an","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1963-1981"},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323793","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":"The Development and Evaluation of a Smartphone-Aided Diagnosis Application to Measure Tympanic Membrane Perforations.","authors":"Lok-Yee Joyce Li, Shin-Yi Wang, Jinn-Moon Yang, Chih-Jou Chen, Cheng-Yu Tsai, Lucas Yee-Yan Wu, Te-Fang Wu, Cheng-Jung Wu","doi":"10.1177/01455613221123361","DOIUrl":"10.1177/01455613221123361","url":null,"abstract":"<p><p>ObjectivesChronic otitis media is a long-term infection of the middle ear. It is characterized by persistent discharge from the middle ear through a perforated tympanic membrane. It is one of the most common causes of preventable hearing loss, especially in developing countries. Precise estimation of the size of tympanic membrane perforation is essential for successful clinical management. In this study, we developed a smartphone-based application to calculate the ratio of the area of tympanic membrane perforation to the area of the tympanic membrane. Twelve standardized patients and 60 medical students were involved to assess the area of tympanic membrane perforation, in particular, the percentage of perforation size.MethodsIn total, 60 student doctors (including year 5 and year 6 medical students, intern and post-graduate year training of doctors) were recruited during their rotation at the Otolaryngology department of Taipei Medical University Shuang-Ho Hospital. Twelve standardized patients with chronic otitis media were recruited through a single otology practice. Oto-endoscopic examination was performed for all patients by using a commercially-available digital oto-endoscope, and clinical images of the tympanic membrane perforation were obtained. To demonstrate the variability of perforation size estimation by different student doctors, we calculated the percentage of perforation using the smartphone-based application for 12 tympanic membranes objectively and compared the results with those visually estimated by the 60 student doctors subjectively.ResultsThe variance in the visual estimation by the 60 student doctors was large. By contrast, variances in smartphone-based application calculations were smaller, indicating consistency in the results obtained from different users. The smartphone-based application accurately estimated the presence of perforation for tympanic membranes with high consistency. The differences in visual estimations can be considerably great and the variances can be large among different individuals.ConclusionsThe smartphone-based application is a dependable tool for precisely evaluating the size of tympanic membrane perforation.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"438-443"},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40629279","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":"","authors":"Suman Pal,&nbsp;Jenna N. Cannata and Jessica L. Rouge*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 13","pages":"962–968 XXX-XXX"},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.accounts.5c00126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516731","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}

{"title":"","authors":"Hao Hu,&nbsp;Hui-Jun Nie and Xiao-Hua Chen*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 13","pages":"962–968 XXX-XXX"},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.accounts.5c00158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516732","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}

{"title":"Novel Mannich-Type Multicomponent Reactions: Discovery, Mechanism, and Application.","authors":"Xianjing Zhou, Zhencheng Lai, Jiaming Li, Chengcheng Fan, Sunliang Cui","doi":"10.1021/acs.accounts.5c00338","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00338","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusThe development of efficient multicomponent reactions (MCRs) represents a vital frontier for the rapid construction of structurally sophisticated molecules from simple precursors in an atom- and step-economic manner. In particular, the Mannich reaction is a prototypical three-component reaction that rapidly assembles a resonance-stabilized carbon nucleophile, an aldehyde (or ketone), and an amine to afford alkylamines and serves as a particularly valuable tool for diversity-oriented synthesis in drug discovery and development. Typically, the nucleophilic components of the Mannich reaction rely on Brønsted-acidic carbonyl C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;3&lt;/sup&gt;)-H and electron-rich aromatic C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt;)-H. However, the development of Mannich reactions involving unactivated C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;3&lt;/sup&gt;)-H remains a formidable challenge, which would be largely attributed to their difficult deprotonation and therefore non-nucleophilic properties.In this Account, we detail the journey from a serendipitous discovery to mechanistic elucidation, wherein an unprecedented double Mannich alkylamination occurred in both C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt;)-H and unactivated benzylic C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;3&lt;/sup&gt;)-H bonds to eventually enable alkylaminative cyclization. Mechanistic studies revealed a distinctive pathway in which a multiple Mannich and &lt;i&gt;retro&lt;/i&gt;-Mannich process and the dehydrogenation of benzylic C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;3&lt;/sup&gt;)-H bonds were key steps to constitute the alkylamination. Enlightened by the mechanistic investigations, our group successfully developed a series of Mannich-type MCRs in which benzofurans/indoles, formaldehyde, and alkylamine hydrochlorides assemble efficiently to furnish piperidine-fused benzofurans/indoles, demonstrating broad compatibility with medicinally relevant functionalities. Inspired by the dual C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt;)-H/C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;3&lt;/sup&gt;)-H alkylaminative cyclization paradigm, we developed a unique Mannich-type MCR of indoles wherein the MCR process occurred in both N-H and the adjacent 2-position C(&lt;i&gt;sp&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt;)-H bonds to access indole-fused seven-membered heterocycles.More importantly, these MCRs serve as a powerful synthetic toolbox in the scaffold evolution of natural products as well as in drug discovery and development. Notably, the modification of natural products (NPs) presents significant challenges due to their inherent structural complexity, and thus efficient synthetic methods could enable more accessible modification of NPs, thereby unlocking their full therapeutic potential. We employed our established MCRs to successfully achieve an innovative scaffold evolution of natural product tanshinones, in which the highly lipophilic tanshinones could be easily transformed to &lt;i&gt;N&lt;/i&gt;-heterocyclic scaffolds with improved functionality, drug-likeness, and biological specificity. As a result, we have pioneered the chemical evolution of Tan I for the discovery of a new class of potent NLRP3 inflammasome i","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537366","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 13","pages":"962–968 XXX-XXX"},"PeriodicalIF":16.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/arv058i013_1953288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516729","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}

{"title":"The Role of Anions in Guanidinium-Catalyzed Chiral Cation Ion Pair Catalysis.","authors":"Wentao Wu, Chu Liu, Choon-Hong Tan, Xinyi Ye","doi":"10.1021/acs.accounts.5c00283","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00283","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusCatalysts drive asymmetric transformations by orchestrating a network of covalent and noncovalent interactions that precisely regulate the reactivity and stereoselectivity. Ion pair catalysis, developed based on the inherent strength and long-range nature of ionic interactions, has demonstrated high catalytic efficiency and broad applicability. While chiral cationic catalysts have long been central to this field, the critical roles of their counteranions have historically been overlooked. Over the past 15 years, we have developed a class of &lt;i&gt;N&lt;/i&gt;-sp&lt;sup&gt;2&lt;/sup&gt;-hybridized guanidinium chiral cation ion pair catalysts, which have been widely applied in enantioselective reactions. In this Account, we present new insights into these catalysts, revealing how the roles of anions, acting as substrates, reagents, and cocatalysts, can be strategically leveraged to achieve remarkable enantioselectivity across a wide range of organic transformations.When acting as substrates, anions, such as sulfinates, thiocarboxylates, and azides, are rendered reactive through intimate ion pairing with the chiral guanidinium moiety. This strategy facilitates desymmetrization processes, exemplified by the conversion of sulfinates to enantioenriched sulfinate esters and the remote desymmetrization of &lt;i&gt;cis&lt;/i&gt;-dibromocyclohexanone via sequential S&lt;sub&gt;N&lt;/sub&gt;2 and acyl transfer steps. Mechanistically, halogenophilic S&lt;sub&gt;N&lt;/sub&gt;2X pathways (e.g., thiocarboxylate substitutions at sterically hindered tertiary carbons) bypass traditional steric limitations, while dynamic kinetic resolution of racemic bromides via azide substitution highlights the interplay between ion exchange and interfacial dynamics.Anions generated &lt;i&gt;in situ&lt;/i&gt; from stoichiometric reagents give rise to highly reactive intermediates such as enolates, sulfenates, and hypervalent silicates, which form ion pairs with chiral cations, enabling enantioselective transformations. For instance, enolates displace tertiary bromides via an S&lt;sub&gt;N&lt;/sub&gt;2X mechanism (frontside attack), circumventing steric hindrance. Sulfur alkylation of sulfenamides yields chiral sulfilimines, while fluoride-activated acylsilanes undergo Brook-like rearrangements through penta-coordinate silicates. Silicon hydrides activated by fluoride form hydridosilicates, enabling enantioselective conjugate reductions of chromones and coumarins. The versatility of ion pairing is further illustrated by α-cyano carbanions in Pd-catalyzed decarboxylative allylic alkylations and is extended to a cooperative catalytic system, where DMAP-generated nucleophiles enable enantioselective phospha-Michael additions via dynamic cation-exchange activation.The utilization of inorganic anions as cocatalysts further expands the scope of chiral cation ion pair catalysis. Peroxytungstate anions synergize with chiral cations to enable the epoxidation of allylic amines, while peroxomolybdate facilitates the &lt;i&gt;N&lt;/i&gt;-oxidation of tertiary amines wi","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525231","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":"Extracellular Aldehyde Sensing Probes for In Vivo Imaging.","authors":"Yingying Ning, Eman A Akam-Baxter, Peter Caravan","doi":"10.1021/acs.accounts.5c00200","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00200","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusCarbonyl-ligation reactions are considered to be largely bioorthogonal due to the rarity of ketones and aldehydes in normal mammalian biology, especially in the extracellular space. However, during development, in wound healing, or in response to many disease conditions, certain extracellular matrix (ECM) proteins can be post-translationally modified by lysyl oxidases to contain aldehyde-bearing side chains. In many diseases, accelerated ECM production is a part of a process called fibrosis (scarring of tissue), and about half of the deaths in the industrialized world arise from disease with a fibrotic component. During fibrogenesis (active fibrosis), lysyl oxidases are upregulated, catalyzing the oxidation of lysine residues on ECM proteins to form lysine aldehyde (allysine, Lys&lt;sup&gt;Ald&lt;/sup&gt;). Lys&lt;sup&gt;Ald&lt;/sup&gt; undergoes condensation reactions with other Lys&lt;sup&gt;Ald&lt;/sup&gt; or Lys residues of adjacent collagens to cross-link proteins. Despite the centrality of fibrogenesis in development and in so many diseases, there is a general lack of tools to noninvasively detect and quantify fibrogenesis in humans or in animal models. Our group used rational design to develop molecular probes for Lys&lt;sup&gt;Ald&lt;/sup&gt; to enable the detection, staging, and treatment monitoring of fibrogenesis. In this Account, we summarize our design strategies and validation methods of Lys&lt;sup&gt;Ald&lt;/sup&gt; targeting probes for applications in a wide range of diseases with a fibroproliferative component.The Lys&lt;sup&gt;Ald&lt;/sup&gt; concentrations exhibit distinct organ- and tissue-specific variations in the progression of fibrogenesis. To increase the sensitivity of Lys&lt;sup&gt;Ald&lt;/sup&gt; probes, we systematically optimized the probe structures to modulate the kinetics of aldehyde condensation reactions and the reverse hydrolysis reaction, molecular hydrophilicity, pharmacokinetics, and elimination. Incorporating electron-withdrawing groups, acidic moieties, and dual-binding ligands significantly enhanced the condensation rates. Combining these strategies with signal amplification by designing \"off-on\" probes, we extended the probe applicability from organs of high Lys&lt;sup&gt;Ald&lt;/sup&gt; levels (lung) to low-concentration systems (liver, tumor, and cardiac tissues). Reducing the hydrolysis rate of the probe-Lys&lt;sup&gt;Ald&lt;/sup&gt; adduct extended the imaging window and permitted the specific detection of Lys&lt;sup&gt;Ald&lt;/sup&gt; in the kidneys. Importantly, our design strategies demonstrate multimodal compatibility, validated through magnetic resonance imaging, positron emission tomography, and fluorescence imaging platforms. The multiscale detection capability in different imaging modalities (cellular to in vivo) provides critical spatial-temporal insights into fibroproliferative disease dynamics in different species and tissues, including onset, progression, and therapeutic response. While this Account focuses on the design of molecular probes for Lys&lt;sup&gt;Ald&lt;/sup&gt;, the strategies employed her","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525230","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}