Bioconjugate Chemistry最新文献

{"title":"Effects of Pretargeting and FcRn Binding Abrogation on the Biodistribution of a One-Armed Antibody-Based T Cell Imaging Agent","authors":"Danielle Mandikian,&nbsp;Lauren Sermeño,&nbsp;Rachana Ohri,&nbsp;Pragya Adhikari,&nbsp;Christopher W. Davies,&nbsp;James T. Koerber,&nbsp;Jason Oeh,&nbsp;Elizabeth Torres,&nbsp;Simon P. Williams,&nbsp;Jack D. Sadowsky and C. Andrew Boswell*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00270","DOIUrl":"10.1021/acs.bioconjchem.5c00270","url":null,"abstract":"<p >Achieving a rapid image contrast is a critical attribute of successful imaging biomarkers of T-cell redirecting cancer immunotherapies, as even small shifts in the cluster of differentiation 8 (CD8) expressing T cell populations can be associated with meaningful therapeutic responses. However, T cell imaging agents, such as one-armed (OA) anti-CD8 monoclonal antibodies, are often limited by high renal uptake and poor resolution against the systemic blood signal. Herein we evaluate antibody pretargeting with and without the abrogation of binding to the neonatal Fc receptor (FcRn) as strategies to enhance the tumor contrast of OA antibodies targeting the minimally internalizing receptor, CD8. Single-photon emission computed tomography (SPECT) imaging of indium-111-labeled tracers in a solid CD8-expressing HPB-ALL tumor-bearing mouse model allowed the impact of FcRn binding to be assessed by both targeted and pretargeted imaging methods. We demonstrated that pretargeted imaging resulted in a higher tumor contrast within hours of tracer administration, irrespective of FcRn binding with reduced renal uptake relative to direct targeting. Abrogation of FcRn binding yielded a higher tumor contrast (relative to blood, kidney, and/or liver) at early time points (less than 2 h) for pretargeted imaging, but with reduced tumor enrichment and increased hepatic signal than in the presence of FcRn binding. Our findings demonstrate that pretargeted imaging with an OA anti-CD8 immunoSPECT tracer can overcome potential imaging liabilities associated with this molecule format, such as high renal uptake and poor resolution against the systemic pool.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1786–1796"},"PeriodicalIF":3.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820119","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":"PD-L1 Aptamer-Functionalized Gold Nanorods for Targeted Combined Chemo-Photothermal Therapy in Breast Cancer","authors":"Hui Xu,&nbsp;Lu Zhao*,&nbsp;Xiaoliang Chen,&nbsp;Zhiqiang Bai,&nbsp;Yanjun Li,&nbsp;Nianping Zhang,&nbsp;Yunfeng Bai* and Feng Feng*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00348","DOIUrl":"10.1021/acs.bioconjchem.5c00348","url":null,"abstract":"<p >The failure of chemotherapy to effectively target cancer cells is a major problem in cancer treatment. Herein, an acidic/near-infrared (NIR) dual-triggered drug release nanoplatform, AuNR/Apt-P@DOX, based on aptamer-functionalized gold nanorods (AuNRs) was reported for actively targeted combined chemo-photothermal therapy. The nanoplatform was prepared by functionalizing AuNRs with the PD-L1 aptamer (Apt-P) and loading DOX, which could be triggered to release under weak acidic conditions and NIR stimulation. Meanwhile, the chemotherapy effect coming from DOX and AuNRs played a vital role in photothermal therapy. The MTT results showed that the fatality rate of MCF-7 cancer cells was up to 80% under the targeting effect of Apt-P. Furthermore, the tumors in mice were almost completely cured under the combined action of photothermal and chemotherapy. This targeted combination therapeutic approach could offer novel insights into the advancement of antitumor strategies for clinical translation.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1854–1864"},"PeriodicalIF":3.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820120","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":"Design, Synthesis, and Preclinical Evaluation of 89Zr/177Lu-FAPI-Tz: A Potential Theranostic Pair Targeting Fibroblast Activation Protein","authors":"Huan Ma,&nbsp;Mingxing Huang,&nbsp;Yingjiang Hu,&nbsp;Jingsong Zhang,&nbsp;Ning Liu,&nbsp;Wei Zhang* and Feize Li*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00369","DOIUrl":"10.1021/acs.bioconjchem.5c00369","url":null,"abstract":"<p >Fibroblast activation protein (FAP)-targeted radioligands have recently emerged as attractive tumor imaging agents. However, the therapeutic applicability of most FAP ligands has been impeded by their short tumor retention. In this study, a tetrazine (Tz)-modified FAPI derivant DOTA-FAPI-Tz was synthesized and radiolabeled with ¹⁷⁷Lu and ⁸⁹Zr to produce ⁸⁹Zr-FAPI-Tz and ¹⁷⁷Lu-FAPI-Tz with high radiochemical purity. Cellular uptake, internalization, efflux, and affinity experiments were performed using the U87MG-FAP cell line (glioma) to evaluate the <i>in vitro</i> FAP-targeting efficacy of the prepared radiotracers. In addition, micro-PET imaging, <i>ex vivo</i> biodistribution, and <i>in vivo</i> anticancer investigations were performed to evaluate the tumor-targeting ability, pharmacokinetic profile, and therapeutic effect of ⁸⁹Zr/¹⁷⁷Lu-FAPI-Tz. The results show that ⁸⁹Zr-FAPI-Tz and ¹⁷⁷Lu-FAPI-Tz demonstrate satisfactory <i>in vitro</i> stability, while ¹⁷⁷Lu-FAPI-Tz has a reduced hydrophilicity compared to ¹⁷⁷Lu-FAPI-04. Consistent with the performance of ¹⁷⁷Lu-FAPI-04, ¹⁷⁷Lu-FAPI-Tz presents rapid and specific FAP-targeting capability but a more significant time-dependent decrease in cellular retention. ⁸⁹Zr-FAPI-Tz and ¹⁷⁷Lu-FAPI-Tz alike display fast tumor localization, showing relatively low radioactivity accumulation in normal organs. Consequently, high-contrast PET images and favorable tumor-to-organ ratios can be obtained. Furthermore, ¹⁷⁷Lu-FAPI-Tz exhibits an effective antitumor efficacy and a satisfactory safety profile in U87MG-FAP tumor-bearing mice. In conclusion, ⁸⁹Zr-FAPI-Tz and ¹⁷⁷Lu-FAPI-Tz are a promising radiopharmaceutical pair for FAP-targeted theranostics, with remarkable tumor accumulation and a favorable pharmacokinetic profile.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1865–1875"},"PeriodicalIF":3.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815283","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":"Synthesis and Preclinical Evaluation of Druglike 18F-Labeled Fibroblast Activation Protein (FAP) Inhibitors with Enhanced Tumor Retention","authors":"Karuna Adhikari,&nbsp;Sergei Grintsevich,&nbsp;Anke de Groot,&nbsp;Emile Verhulst,&nbsp;Yentl van Rymenant,&nbsp;Christel Vangestel,&nbsp;Louis Lauwerys,&nbsp;Alan Miranda,&nbsp;Ingrid De Meester,&nbsp;Pieter Van der Veken and Filipe Elvas*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00366","DOIUrl":"10.1021/acs.bioconjchem.5c00366","url":null,"abstract":"<p >Fibroblast activation protein (FAP) is upregulated in cancer and fibrosis, making it an ideal target for imaging and therapy. Most FAP radioligands are large, highly polar, chelator-based molecules that suffer from limited tissue penetration and rapid tumor washout. In this study, we developed two covalently ¹⁸F-labeled, druglike FAP inhibitors, [¹⁸F]<b>5a</b> and [¹⁸F]<b>5b</b>, featuring quaternary ammonium moieties linked via PEG chains to enhance tumor retention while maintaining high selectivity and favorable pharmacokinetics. Both radiotracers showed high affinity and specific uptake <i>in vitro</i> and <i>in vivo</i>. Compared to the clinically used [¹⁸F]AlF-NOTA-FAPI-74, [¹⁸F]<b>5a</b> and [¹⁸F]<b>5b</b>, exhibited significantly improved tumor retention at 6 h p.i. ([¹⁸F]<b>5a</b>: 4.48 ± 0.34%IA/g; [¹⁸F]<b>5b</b>: 6.70 ± 0.22%IA/g and [¹⁸F]AlF-NOTA-FAPI-74:0.54 ± 0.08%IA/g). These findings highlight the importance of polarity tuning and the utility of quaternary ammonium groups for obtaining sustained tumor retention. They offer a valuable design strategy for novel radiotheranostic ligands that contain covalently bound radionuclides for imaging and treatment of FAP-positive tumors.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1887–1906"},"PeriodicalIF":3.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820133","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":"Harnessing Fc-Directed Bioconjugation for the Synthesis of Site-Specifically Modified Radioimmunoconjugates","authors":"Camilla Grimaldi,&nbsp;Joni Sebastiano,&nbsp;Wei-Siang Mark Kao,&nbsp;Emilia Strugala,&nbsp;Shane A. McGlone,&nbsp;Tomohiro Watanabe,&nbsp;Tsubasa Aoki,&nbsp;Tomohiro Fujii and Brian M. Zeglis*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00306","DOIUrl":"10.1021/acs.bioconjchem.5c00306","url":null,"abstract":"<p >A growing body of preclinical and clinical evidence has shown that site-specifically and site-selectively modified immunoconjugates exhibit improved <i>in vivo</i> performance compared to their stochastically modified cousins. However, extant approaches to site-specific bioconjugation suffer from a variety of issues that make clinical translation challenging, including instability, complexity, and expense. Herein, we describe a novel chemical approach to the synthesis of site-specifically modified radioimmunoconjugates that is simple and straightforward. To this end, we leveraged an Fc-directed peptide to append free sulfhydryl moieties to unique sites within the Fc domain of the CA19-9-targeting antibody 5B1. These thiols were then modified with phenyloxadiazolyl methylsulfone-bearing variants of the chelator CHX-A″-DTPA, and the immunoconjugate was radiolabeled with [¹⁷⁷Lu]Lu³⁺ to produce [¹⁷⁷Lu]Lu-DTPA-^PODSAJICAP-5B1 in high yield, purity, and specific activity. Subsequent analyses confirmed the site-specificity of the modification and demonstrated the high stability and immunoreactivity of the radioimmunoconjugate. Biodistribution studies in athymic nude mice bearing subcutaneous BxPC3 pancreatic cancer xenografts revealed that [¹⁷⁷Lu]Lu-DTPA-^PODSAJICAP-5B1 produced high activity concentrations in tumor tissue as well as high tumor-to-background activity concentration ratios and displayed performance that compared favorably to ¹⁷⁷Lu-labeled analogues synthesized with traditional stochastic and thiol-selective bioconjugation strategies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1588–1594"},"PeriodicalIF":3.9,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802977","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":"Exploring 18F/19F Isotopic Exchange for the Synthesis of [18F]Trifluoromethylated Arenes","authors":"Xinlin Zhong,&nbsp;Junjie Yan*,&nbsp;Chen Su,&nbsp;Wei Xu,&nbsp;Xiang Ding,&nbsp;Xinyu Wang,&nbsp;Donghui Pan,&nbsp;Yuping Xu,&nbsp;Lizhen Wang,&nbsp;Chongyang Chen and Min Yang*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00374","DOIUrl":"10.1021/acs.bioconjchem.5c00374","url":null,"abstract":"<p >The presence of the trifluoromethyl aromatic (Ar–CF₃) moiety can enhance the interactions with targets, membrane permeability, metabolic stability, and drug efficacy. It also prioritizes positron emission tomography (PET) imaging without altering original drug structures. Although the simplicity of ¹⁸F/¹⁹F isotope exchange has flourished in boron-, silicon-, phosphorus- and sulfur-based ¹⁸F-radiochemistry, its application to CF₂(sp³)–¹⁸F bond formation remains challenging. Herein, we reported the radiolabeling of Ar–CF₃ derivatives via ¹⁸F/¹⁹F isotopic exchange across a range of substrates (13 examples), achieving favorable nondecay corrected radiochemical yields (up to 27.2 ± 1.3%) and molar activities (2.8 ± 0.2 GBq·μmol^–1). The utility of this isotopic exchange-based strategy for trifluoromethylated arene molecules was further demonstrated through the radiolabeling of other Ar–CF₃-containing molecules including ponatinib, and through PET imaging using ¹⁸F-labeled selinexor. Overall, this in situ ¹⁸F-radiolabeling strategy for Ar–CF₃-containing small molecules expands the scope for developing new PET tracers, demonstrates potential application in drug discovery, and offers an efficient approach for synthesizing small-molecule tracers for PET imaging.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1876–1886"},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797638","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":"Polymeric Nanocarriers Functionalized with Peptides for Improved Glioblastoma Targeting and Blood–Brain Barrier Permeability","authors":"Cristian Antonio Wieczorek Villas Boas,&nbsp;Aaron Priester,&nbsp;Buck E. Rogers and Anthony J. Convertine*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00119","DOIUrl":"10.1021/acs.bioconjchem.5c00119","url":null,"abstract":"<p >We report the synthesis of polymeric conjugates designed to penetrate the blood–brain barrier (BBB) and selectively bind glioblastoma (GBM) cells through reversible addition–fragmentation chain transfer (RAFT) polymerization. The resulting materials were engineered to contain peptide macromonomers for cell-specific targeting and integrated DOTA units to facilitate radiolabeling with copper-64 (⁶⁴Cu), yielding radiolabeled conjugates with greater than 95% radiochemical purity. In biodistribution assessments conducted in mice, C1C2 peptide-conjugated polymers showed significantly improved accumulation in brain tissue, supported by brain perfusion analyses confirming efficient BBB penetration. Additionally, flow cytometry evaluations demonstrated specific affinity of GBM-targeted polymer formulations toward U87 glioblastoma cells. Overall, these polymer–peptide conjugates─particularly the C1C2-functionalized variant─demonstrate notable promise for targeted imaging and therapy of glioblastoma, providing a foundation for future preclinical development.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1639–1648"},"PeriodicalIF":3.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797639","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":"Development of “Furan Warhead”-Equipped Antagonistic Nanobodies for Covalent Cross-Linking to the Epidermal Growth Factor Receptor","authors":"Laure Tack,&nbsp;Laia Miret-Casals,&nbsp;Olivier Zwaenepoel,&nbsp;Enrico Cadoni,&nbsp;Marleen Van Troys,&nbsp;Jan Gettemans* and Annemieke Madder*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00144","DOIUrl":"10.1021/acs.bioconjchem.5c00144","url":null,"abstract":"<p >Covalent therapeutics have gained attention in drug design, as they have the potential to result in enhanced potency and prolonged duration of action. However, the safety concerns associated with off-target effects have long been a serious hurdle for covalent drug design. Proximity-enabled covalent bond formation combined with the use of caged warheads offers an attractive strategy in this context. We here report on the use of the proximity-dependent furan-oxidation-based cross-linking and a previously reported antagonistic nanobody (EgA1), to design new nanobodies that covalently trap the soluble fraction of the epidermal growth factor receptor (sEGFR). The furan-containing EgA1 nanobodies were validated for binding to serum(s)EGFR via biomolecular binding assays. Their singlet oxygen-induced cross-linking behavior toward the sEGFR protein was evaluated <i>in vitro</i> through photosensitizer irradiation. Initial experiments using an alternative biocompatible Rose Bengal derivative as photosensitizer further show proof of concept for the use of such furan-containing nanobodies for covalent trapping of the EGFR present on the plasma membrane of MDA-MB-231 breast cancer cells.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1649–1660"},"PeriodicalIF":3.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787803","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":"Interfacial Engineering of a NaGdF4@NaYF4:Nd3+-Reinforced PVA/Chitosan Janus Hydrogel for Osteosarcoma and Osseointegration via the Entrapment of Strontium in Bisphosphonates","authors":"Deepa Murugan,&nbsp;M. Ezhilan,&nbsp;Abhishek Kumar,&nbsp;Arunkumar Dhayalan and S. Kannan*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00302","DOIUrl":"10.1021/acs.bioconjchem.5c00302","url":null,"abstract":"<p >Postoperative impacts after osteosarcoma excision such as tumor recurrence and critical-sized bone defects continue to pose significant therapeutic challenges. Conventional implants employed to treat these defects often pose negligence in eliminating the residual tumor cells. The current study aims to address these constraints through the development of a multifunctional Janus hydrogel. An alendronate strontium complex and NaGdF₄@NaYF₄:Nd³⁺ nanophosphors have been incorporated in the poly(vinyl alcohol) (PVA)/chitosan matrix to attain the desired therapeutic and diagnostic functions. The apatite-forming ability evidenced through the SBF immersion studies alongside the multimodal imaging capabilities, namely, MRI, CT, and NIR luminescence of the Janus hydrogel, is deduced from the investigation. The ability of nanophosphors to generate localized hyperthermia of ∼56.1 °C under 808 nm near-infrared (NIR) irradiation led to the ablation of osteosarcoma cells. The conjugated alendronate supports intrinsic cytotoxicity in MG63 cells, even in the absence of irradiation. Furthermore, the biocompatibility and osteogenesis capacity of the hydrogel are evidenced through the enhanced HEK293 and MG63 cell proliferation under an osteogenic medium alongside the attainment of elevated levels of osteogenic markers such as RUNX2 and COL1 and calcium matrix mineralization. The overall findings highlight the complementary role of the Janus hydrogel in eliminating the tumor cells, promoting bone regeneration and angiogenesis.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1838–1853"},"PeriodicalIF":3.9,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774313","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":"Navigating Dipeptide by a Nucleoside Moiety: A Promising Way for Enhancing Antioxidative Effect against Radical-Induced DNA Oxidation","authors":"Peng-Fei Zhao,&nbsp; and ,&nbsp;Zai-Qun Liu*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00290","DOIUrl":"10.1021/acs.bioconjchem.5c00290","url":null,"abstract":"<p >Construction of novel antioxidants against radical-induced oxidation of DNA is still challenging, though we have elucidated that the Ugi four-component reaction (Ugi 4CR) acts as an efficient way for achieving antioxidative dipeptides with caffeic, ferulic, sinapic, and syringic acids being the antioxidative functional groups. Herein, as an ongoing exploration on the designing of nucleoside-appended antioxidants, dipeptides accessed from the Ugi 4CR are applied for the connection with 5′-OH of a nucleoside moiety with a succinate being the linkage. Antioxidative effects of the afforded nucleoside-appended dipeptides are enhanced 2∼3-fold compared to their parent dipeptides when they are used to protect DNA against the peroxyl-radical-induced oxidation. This is ascribed to the introduction of a nucleoside moiety into the antioxidative dipeptide enabling navigation of the dipeptide to intercalate with the DNA strand more tightly, and the hydroxy and amino groups in the nucleoside moiety are beneficial for the nucleoside-appended dipeptide to scavenge radicals. Thus, the navigation of Ugi 4CR products by a nucleoside moiety is shown to be a versatile approach for accessing novel antioxidants that are able to protect DNA against radical-induced oxidation more efficiently.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1807–1819"},"PeriodicalIF":3.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758691","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}