Bioconjugate Chemistry最新文献

{"title":"Ferritin versus Liposomes: A Comparative Analysis of Protein- and Lipid-Based Drug Delivery Systems.","authors":"Yang Liu, Feiyan Zhu, Jiuyang He, Minmin Liang","doi":"10.1021/acs.bioconjchem.4c00576","DOIUrl":"10.1021/acs.bioconjchem.4c00576","url":null,"abstract":"<p><p>Drug delivery systems (DDSs) are crucial for the controlled release and targeted delivery of therapeutic agents, enhancing the stability and specificity of small molecules, nucleic acids, or peptides and addressing challenges such as drug instability and poor tissue targeting, particularly in oncology. Over the past few decades, liposomes have become one of the most widely used DDSs due to their unique physicochemical properties and biocompatibility. In the 1990s, liposomes were approved by the FDA as the first nanomedicine for disease treatment. Ferritin, a natural protein with a hollow nanocage structure, shares many similarities in architecture and functionality with liposomes. As an innovative DDS, ferritin offers distinct advantages including inherent tumor-targeting capabilities and exceptional biocompatibility. Liposomes and ferritin represent, respectively, established and emerging approaches in drug delivery, both excelling in key features like encapsulation efficiency and biocompatibility, which align with the standards for pharmaceutical carriers. While liposomal formulations have been clinically used, challenges such as precision targeting remain unresolved. In contrast, although ferritins hold considerable promise for drug delivery, they have not yet been implemented in clinical practice. In this review, we provide a comprehensive analysis of ferritins and liposomes as drug delivery vehicles, evaluating their drug-loading capacities, tumor-targeting capabilities, biocompatibility, and therapeutic potential. On the basis of a comparison of their intended applications and inherent limitations in the context of current treatment strategies, ferritin is expected to be an ideal delivery vehicle for tumor-targeted therapy and a strong candidate for clinical translation in the near future.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"127-135"},"PeriodicalIF":4.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Site-Specific Protein Modification via Reductive Amination of Genetically Encoded Aldehyde","authors":"Lei Zhao,&nbsp;Zhifen Huang,&nbsp;Haonan Meng,&nbsp;Qianzhi Liang,&nbsp;Xun-Cheng Su and Weimin Xuan*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0053810.1021/acs.bioconjchem.4c00538","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00538https://doi.org/10.1021/acs.bioconjchem.4c00538","url":null,"abstract":"<p >Aldehyde represents an extremely useful bio-orthogonal group in chemical biology and has promoted the generation of high-quality bioconjugates in therapeutics development. However, the installation of an aldehyde group on a protein and subsequent conjugation remains technically inadequate in the aspect of site choice, substrate availability, and linkage stability. Herein, we take efforts to advance the genetic incorporation of an aldehyde-containing noncanonical amino acid in <i>E. coli</i> and then show that reductive amination could be a useful reaction in introducing various amine-containing molecules, including peptides, into a specific site of proteins.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 3","pages":"377–382 377–382"},"PeriodicalIF":4.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Phosphoribosyl Ubiquitin Probes Targeting Legionella Dup Enzymes","authors":"Max S. Kloet,&nbsp;Rishov Mukhopadhyay,&nbsp;Rukmini Mukherjee,&nbsp;Mohit Misra,&nbsp;Cami M. P. Talavera Ormeño,&nbsp;Rayman T. N. Tjokrodirijo,&nbsp;Paul J. Hensbergen,&nbsp;Peter A. van Veelen,&nbsp;Ivan Đikić,&nbsp;Aysegul Sapmaz and Gerbrand J. van der Heden van Noort*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0054110.1021/acs.bioconjchem.4c00541","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00541https://doi.org/10.1021/acs.bioconjchem.4c00541","url":null,"abstract":"<p >In order to effectively replicate within a host cell, the <i>Legionella pneumophila</i> bacterium secretes effector enzymes into the cytoplasm in order to manipulate cellular host pathways including host ubiquitination. Some of these effectors, the so-called SidE-family, mediate noncanonical phosphoribosyl serine ubiquitination (PR-ubiquitination) of host substrate proteins, contributing to the recruitment of ER-remodeling proteins and the formation of a <i>Legionella</i>-containing vacuole, which is crucial in the early stages of bacterial infection. PR-ubiquitination is a dynamic process that is reversed by other <i>Legionella</i> effectors called deubiquitinases for PR-ubiquitination (Dups). We recently discovered a reactive allosteric cysteine in close proximity to the catalytic triad of DupA, which can be exploited as a target for covalent probe development. We here report on the synthesis of vinyl-sulfonate and fluoro-sulfonate warhead-containing phosphoribosyl ubiquitin probes, where the Arg42 position of ubiquitin is linked to the C1 of ribose via a native guanidinium group, and compare them to triazole-linked probes. In vitro tests on recombinant DupA and SdeA_PDE revealed that these probes are able to capture the enzymes covalently. In a pull-down proteomics experiment, DupA and DupB enzymes are enriched from <i>Legionella</i>-infected cell lysates, highlighting the potential of native Arg-riboside linked probes to capture <i>Legionella</i> effector enzymes in a complex proteome.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 3","pages":"457–463 457–463"},"PeriodicalIF":4.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00541","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Delivery of TLR7 Agonists to the Tumor Microenvironment Enhances Tumor Immunity via Activation of Tumor-Resident Myeloid Cells","authors":"Emanuela Sega,&nbsp;Srikanth Kotapati,&nbsp;Yam B. Poudel,&nbsp;Qinqin Cheng,&nbsp;Keerthi Sadanala,&nbsp;Bridget Schneider,&nbsp;Eugene P. Chekler,&nbsp;Chetana Rao,&nbsp;Sanjeev Gangwar,&nbsp;Tim Sproul,&nbsp;Deborah Law,&nbsp;Miranda Broz,&nbsp;Pavel Strop and Sayumi Yamazoe*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0053410.1021/acs.bioconjchem.4c00534","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00534https://doi.org/10.1021/acs.bioconjchem.4c00534","url":null,"abstract":"<p >Toll-like receptors (TLR) are phylogenetically conserved mediators of innate immunity that are essential for establishing adaptive immune responses against invading pathogens. TLR7 is an endosomal receptor expressed predominantly in myeloid and B cells. Activation of TLR7 induces Type I interferon and proinflammatory responses; therefore, targeting TLR7 is a promising strategy for antitumor therapy. Although the use of bacterial components to trigger innate immune responses in cancer patients started a century ago, the effectiveness of systemic TLR agonists has been rather underwhelming in clinical trials, partly due to nonspecific immune activation leading to safety and tolerability issues. Antibody–drug conjugates (ADCs) constitute a proven therapeutic modality amenable to systemic administration with limited toxicity concerns via a targeted delivery platform. We generated TLR7 agonist–antibody conjugates that recognize tumor antigens expressed on the surface of tumor cells. Generated ADCs demonstrated robust activity in in vitro tumor antigen-presenting cell (APC) coculture systems as indicated by dose-dependent upregulation of PD-L1 and CD86 on macrophages. TLR7 agonist-ADC provided superior tumor growth control compared to intravenously (IV) administrated free TLR7 agonist. Treatment with TLR7 agonist-ADC led to prolonged activation of myeloid cells in the tumor microenvironment (TME) with minimum immune activation in the periphery. Systemic and tissue exposure studies demonstrated tumor-specific free drug release by targeted ADC treatment. In summary, the TLR7 agonist-ADC can potentially activate immune cells in the TME to generate tumor antigen-specific T-cell responses, making it an attractive approach for precision cancer therapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 3","pages":"437–448 437–448"},"PeriodicalIF":4.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00534","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid Nanocarriers as Precision Delivery Systems for Brain Tumors","authors":"Roshan Keshari,&nbsp;Mahima Dewani,&nbsp;Navneet Kaur,&nbsp;Girijesh Kumar Patel,&nbsp;Sumit Kumar Singh,&nbsp;Pranjal Chandra*,&nbsp;Rajendra Prasad* and Rohit Srivastava*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0000710.1021/acs.bioconjchem.5c00007","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00007https://doi.org/10.1021/acs.bioconjchem.5c00007","url":null,"abstract":"<p >Brain tumors, particularly glioblastomas, represent the most complicated cancers to treat and manage due to their highly invasive nature and the protective barriers of the brain, including the blood-brain barrier (BBB). The efficacy of currently available treatments, viz., radiotherapy, chemotherapy, and immunotherapy, are frequently limited by major side effects, drug resistance, and restricted drug penetration into the brain. Lipid nanoparticles (LNPs) have emerged as a promising and targeted delivery system for brain tumors. Lipid nanocarriers have gained tremendous attention for brain tumor therapeutics due to multiple drug encapsulation abilities, controlled release, better biocompatibility, and ability to cross the BBB. Herein, a detailed analysis of the design, mechanisms, and therapeutic benefits of LNPs in brain tumor treatment is discussed. Moreover, we also discuss the safety issues and clinical developments of LNPs and their current and future challenges. Further, we also focused on the clinical transformation of LNPs in brain tumor therapy by eliminating side effects and engineering the LNPs to overcome the related biological barriers, which provide personalized, affordable, and low-risk treatment options.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 3","pages":"347–366 347–366"},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functionalization of Biomimetic Polydopamine Shells Constructed onto Bismuth-Core Particles for pH-Mediated Drug Targeting to Heal Bacterial Infections","authors":"Md. Abdur Rahman*,&nbsp;Pinky Akter,&nbsp;Md. Rowshanul Habib,&nbsp;Md. Ataur Rahman,&nbsp;Md. Mahiuddin,&nbsp;Md. Mahbubor Rahman,&nbsp;Md. Shahidul Islam,&nbsp;M. A. Jalil Miah and Hasan Ahmad,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0000310.1021/acs.bioconjchem.5c00003","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00003https://doi.org/10.1021/acs.bioconjchem.5c00003","url":null,"abstract":"<p >Nonhealing chronic bacterial infections are very challenging to both patients and the healthcare-providing system. Multimodal therapy enhances the antibiotic efficacy to treat infections via combating multidrug resistance through cumulative therapeutic effects. Functionalized polydopamine (PDA)-coated Bi particles having a core–shell structure may treat such chronic infections. We fabricated a new advanced material based on Tris-functionalized PDA and Bi using a facile three-step protocol for healing drug-resistant bacterial infections. The fabrication of Bi particles, PDA coating on Bi particles, and their Tris functionalization were confirmed by X-ray diffraction, and spectroscopic and thermogravimetric analyses. Tris-functionalized PDA-coated Bi particles, abbreviated as Bi/PDA-Tris, exhibited a higher average diameter, improved hydrophilicity, aqueous dispersity, and colloidal stability. Bi/PDA-Tris showed a delicate surface morphology, narrow size distribution, spherical shape, and core–shell structure. <i>In vitro</i> bovine serum albumin and hemolysis assays showed minimal protein adsorption and the desirable hemocompatibility of Bi/PDA-Tris. Antibacterial gentamicin (GM)-immobilized Bi/PDA-Tris showed pH-mediated sustained drug release kinetics under acidic conditions. The <i>in vitro</i> study of GM-loaded Bi/PDA-Tris particles exhibited significant bacterial growth inhibition and bactericidal activity. Tris functionalization effectively enhances the antibacterial efficacy of the PDA shell under acidic conditions to target and heal bacterial infections. This approach has introduced economic, nontoxic, easy-to-use, relatively more biocompatible Bi particles as a substituent for precise metals like Pt, Au, and Ag for the development of core–shell composite materials.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 3","pages":"563–577 563–577"},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferritin versus Liposomes: A Comparative Analysis of Protein- and Lipid-Based Drug Delivery Systems","authors":"Yang Liu,&nbsp;Feiyan Zhu,&nbsp;Jiuyang He* and Minmin Liang*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0057610.1021/acs.bioconjchem.4c00576","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00576https://doi.org/10.1021/acs.bioconjchem.4c00576","url":null,"abstract":"<p >Drug delivery systems (DDSs) are crucial for the controlled release and targeted delivery of therapeutic agents, enhancing the stability and specificity of small molecules, nucleic acids, or peptides and addressing challenges such as drug instability and poor tissue targeting, particularly in oncology. Over the past few decades, liposomes have become one of the most widely used DDSs due to their unique physicochemical properties and biocompatibility. In the 1990s, liposomes were approved by the FDA as the first nanomedicine for disease treatment. Ferritin, a natural protein with a hollow nanocage structure, shares many similarities in architecture and functionality with liposomes. As an innovative DDS, ferritin offers distinct advantages including inherent tumor-targeting capabilities and exceptional biocompatibility. Liposomes and ferritin represent, respectively, established and emerging approaches in drug delivery, both excelling in key features like encapsulation efficiency and biocompatibility, which align with the standards for pharmaceutical carriers. While liposomal formulations have been clinically used, challenges such as precision targeting remain unresolved. In contrast, although ferritins hold considerable promise for drug delivery, they have not yet been implemented in clinical practice. In this review, we provide a comprehensive analysis of ferritins and liposomes as drug delivery vehicles, evaluating their drug-loading capacities, tumor-targeting capabilities, biocompatibility, and therapeutic potential. On the basis of a comparison of their intended applications and inherent limitations in the context of current treatment strategies, ferritin is expected to be an ideal delivery vehicle for tumor-targeted therapy and a strong candidate for clinical translation in the near future.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 2","pages":"127–135 127–135"},"PeriodicalIF":4.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delivery of Tempol from Polyurethane Nanocapsules to Address Oxidative Stress Post-Injury","authors":"Temitope Ale,&nbsp;Tolulope Ale,&nbsp;Kimberly J. Baker,&nbsp;Kameel M. Zuniga,&nbsp;Jack Hutcheson and Erin Lavik*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0036010.1021/acs.bioconjchem.4c00360","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00360https://doi.org/10.1021/acs.bioconjchem.4c00360","url":null,"abstract":"<p >Traumatic brain injuries (TBIs) result in significant morbidity and mortality due to the cascade of secondary injuries involving oxidative stress and neuroinflammation. The development of effective therapeutic strategies to mitigate these effects is critical. This study explores the fabrication and characterization of polyurethane nanocapsules for the sustained delivery of Tempol, a potent antioxidant. The nanocapsules were designed to extend the release of Tempol over a 30-day period, addressing the prolonged oxidative stress observed post-TBI. Tempol-loaded polyurethane nanocapsules were synthesized using interfacial polymerization and nanoemulsion techniques. Two generations of nanocapsules were produced, differing in Tempol loading and PEGylation levels. The first generation, with lower Tempol loading, exhibited an average size of 159.8 ± 12.61 nm and a Z-average diameter of 771.9 ± 87.95 nm. The second generation, with higher Tempol loading, showed an average size of 141.4 ± 6.13 nm and a Z-average diameter of 560.7 ± 171.1 nm. The zeta potentials were −18.9 ± 5.02 mV and −11.9 ± 3.54 mV for the first and second generations, respectively. Both generations demonstrated the presence of urethane linkages, confirmed by Fourier Transform Infrared Spectroscopy (FTIR). Loading studies revealed Tempol concentrations of 61.94 ± 3.04 μg/mg for the first generation and 77.61 ± 3.04 μg/mg for the second generation nanocapsules. Release profiles indicated an initial burst followed by a sustained, nearly linear release over 30 days. The higher PEGylation in the second generation nanocapsules is advantageous for intravenous administration, potentially enhancing their therapeutic efficacy in TBI treatment. This study demonstrates the feasibility of using polyurethane nanocapsules for the prolonged delivery of Tempol, offering a promising approach to manage oxidative stress and improve outcomes in TBI patients. Future work will include testing these nanocapsules in vivo to determine their potential at modulating recovery from TBI.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 2","pages":"146–151 146–151"},"PeriodicalIF":4.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Method for Screening Sodium Cyanoborohydride for Free Cyanide Content and Its Impact on Bioconjugation Chemistry","authors":"Jarrod P. Cohen*,&nbsp;Adam DiCaprio,&nbsp;Jian He,&nbsp;Mikhail Reibarkh,&nbsp;James Small and Matthew Schombs,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0051410.1021/acs.bioconjchem.4c00514","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00514https://doi.org/10.1021/acs.bioconjchem.4c00514","url":null,"abstract":"<p >Sodium cyanoborohydride (CBH) is commonly used as a mild reducing agent in the reductive amination of aldehydes and free amines. Within the pharmaceutical industry, this reaction is employed in the bioconjugation of proteins and peptides. Free cyanide species such as HCN and NaCN are known residual impurities in CBH that can contribute to the formation of undesired side products including cyanoamines and cyanohydrins. In commercial processes, the potential for bound cyanated species requires an analytical control strategy to monitor and mitigate any risk to human health. Given these concerns, minimization of cyanated side products is of utmost priority and can be achieved through a robust control strategy of quantitative screening of starting materials for free cyanide. Alternative risk mitigation strategies such as purification of bound cyanide containing species to pure species are less effective due to minor chemical differences between the expected product and bound cyanide species. Herein, we present a simple chromatographic assay for the quantitation of free cyanide in the raw material sodium cyanoborohydride. Method development, robustness evaluation, and scientific soundness assessment are reported with excellent linearity, accuracy, precision, and specificity. Additionally, this method was applied for the evaluation of raw material supplied from 10 commercial sources, none of which report a specification for free cyanide within their certificate of analysis. The measured free cyanide from these vendors ranged from 8 to 80 mM concentration, thereby confirming the value of screening these raw materials. Finally, we demonstrate the impact of free cyanide on a model bioconjugation reaction between ornithine and glyceraldehyde.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 2","pages":"245–252 245–252"},"PeriodicalIF":4.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Transiently Strainable Benzocycloheptenes for Catalyst-Free, Visible-Light-Mediated [3 + 2]-Cycloadditions","authors":"Shivangi Kharbanda,&nbsp;Osaid Alkhamayseh,&nbsp;Georgia Eastham and Jimmie D. Weaver*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0059510.1021/acs.bioconjchem.4c00595","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00595https://doi.org/10.1021/acs.bioconjchem.4c00595","url":null,"abstract":"<p >Dynamic photogeneration of ephemeral and reactive species is enabling for chemical reactions, providing spatial and temporal control. A previous study from our group established the ability of 6,7-dihydro-5H-benzo[7]annulene, benzocycloheptene (<b>BC7</b>), to convert photochemical energy into ring strain, enabling the rapid cycloaddition of alkyl azides with the reversibly formed and transient <i>trans</i>-isomer, affording versatile nonaromatic triazolines. Despite the conceptual advances of the previous study, some challenges remained: the fragility of the triazoline products, the low regioselectivity for the cycloaddition, a need for an iridium-based photosensitizer and organic-based solvents, and a lack of convenient linchpin functional group handles. Herein, we communicate the development of a second generation of <b>BC7</b> molecules that overcome the issues of the first generation. A method to convert fragile triazoline products to stable triazoles was developed. The alkene component was polarized with a carbonyl group, dramatically improving the regioselectivity while simultaneously red-shifting the absorbance of the cycloalkene into the visible region, which was expected to facilitate direct excitation and eliminate the need for photocatalysts. However, experiments indicated that the cycloaddition involved passage through a triplet manifold, complicating the direct excitation strategy. This was successfully overcome by attaching a bromine atom directly to the alkene moiety, which accelerated singlet-to-triplet intersystem crossing by the heavy atom effect. Further exploration identified sites of substitution that can increase the water solubility and provide a handle for the loading of chemical tools and probes.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 2","pages":"302–308 302–308"},"PeriodicalIF":4.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}