Bioorganic Chemistry最新文献_第10页

Design, synthesis, and biological evaluation of novel selenium-matrine hybrid compounds as topo I -targeted anticancer agents. 新型硒-苦参碱杂化物拓扑靶向抗癌药物的设计、合成及生物学评价。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-06-27 DOI: 10.1016/j.bioorg.2026.110173

Jixiang Xiao, Fei Li, Huan Gao, Junzhong Yin, Yichen Xue, Zhengbin Tang, Chunmei Liu, Jianyu Zhou, Xiaoping Zhou, Di Liang

{"title":"Design, synthesis, and biological evaluation of novel selenium-matrine hybrid compounds as topo I -targeted anticancer agents.","authors":"Jixiang Xiao, Fei Li, Huan Gao, Junzhong Yin, Yichen Xue, Zhengbin Tang, Chunmei Liu, Jianyu Zhou, Xiaoping Zhou, Di Liang","doi":"10.1016/j.bioorg.2026.110173","DOIUrl":"10.1016/j.bioorg.2026.110173","url":null,"abstract":"The natural product matrine remains one of the most widely utilized scaffolds in drug discovery and development. Numerous reported derivatives have demonstrated potent topoisomerase inhibitory activity along with promising anticancer effects. Selenium, an essential trace element in living organisms, plays critical physiological roles. Emerging evidence suggests that incorporation of selenium atoms into anticancer agents can substantially enhance their biological potency, positioning this approach as an innovative and effective strategy in modern anticancer drug design. In the present study, we rationally designed and synthesized two series of 30 novel selenium-matrine hybrid compounds by strategically introducing selected selenium-containing functionalities (-SeCN or -SeCF₃) into the matrine skeleton. Among these hybrids, compounds 5l and 5n exhibited particularly strong inhibition of cancer cell proliferation and migration, accompanied by significant topoisomerase I (Topo I) inhibitory activity. Mechanistic investigations revealed that 5l and 5n induce DNA damage and elevate intracellular ROS, leading to mitochondrial dysfunction, G1-phase cell cycle arrest, and apoptosis. Molecular docking studies combined with molecular dynamics simulations further confirmed that both compounds form stable and favorable interactions with the Topo I-DNA complex. Additionally, a preliminary evaluation of the physicochemical properties of the lead compound was performed through in silico prediction of relevant physical and chemical parameters. Acute toxicity assessments and histopathological examinations demonstrated that 5n possesses acceptable in vivo safety profiles. Collectively, these findings establish a solid theoretical and experimental foundation for the future optimization of related derivatives and their advancement into further preclinical development.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110173"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual-Chelator conjugates for [⁶⁸Ga]Ga- and [¹⁷⁷Lu]Lu-based PSMA Radiotheranostics. [68Ga]Ga-和[177Lu] lu -基PSMA放射治疗的双螯合剂共轭物。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-10 DOI: 10.1016/j.bioorg.2026.110236

Wenbin Jin, Yang Luo, Zhaohui Zhu, Lin Zhu, Hank F Kung

{"title":"Dual-Chelator conjugates for [68Ga]Ga- and [177Lu]Lu-based PSMA Radiotheranostics.","authors":"Wenbin Jin, Yang Luo, Zhaohui Zhu, Lin Zhu, Hank F Kung","doi":"10.1016/j.bioorg.2026.110236","DOIUrl":"10.1016/j.bioorg.2026.110236","url":null,"abstract":"Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer (PCa) and represents an attractive target for radiotheranostic applications. While conventional approaches often convert PSMA-targeted imaging agents into therapeutic counterparts through chelator substitution, we explored a dual-chelator strategy by integrating HBED-CC and DOTA into the PSMA-093 scaffold. This design generated three dual-chelator conjugates (1-3) capable of supporting the chelation of both diagnostic and therapeutic radionuclides within a single molecular platform. The compounds were successfully radiolabeled with [68Ga]Ga3+ and [177Lu]Lu3+, and mass spectrometric analysis confirmed site-selective coordination of Ga3+ by HBED-CC and Lu3+ by DOTA. All conjugates retained high PSMA-binding affinity in vitro, with [68Ga]Ga/[177Lu]Lu-2 and [68Ga]Ga/[177Lu]Lu-3 demonstrating enhanced cellular uptake in 22Rv1-FOLH-oe (PSMA overexpression) cells. In vivo PET/CT imaging and biodistribution studies revealed that [68Ga]Ga-2 exhibited favorable pharmacokinetics, including rapid background clearance and improved tumor retention. Importantly, [177Lu]Lu-2 achieved high tumor uptake, reaching 8.35%ID/g at 24 h post-injection, indicating effective tumor targeting and prolonged retention. These findings support the dual-chelator strategy as a promising platform for the development of next-generation PSMA-targeted radiotheranostic agents. By enabling efficient integration of diagnostic imaging and radionuclide therapy within a single molecule, this approach offers enhanced flexibility for radiopharmaceutical design while preserving favorable biological performance. The dual-chelator concept may facilitate the development of more effective companion diagnostic-therapeutic pairs and contribute to the advancement of precision oncology.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110236"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biogenesis, structural diversity, biosynthesis and bioactivities of linear peptides from cyanobacteria. 蓝藻线状肽的生物发生、结构多样性、生物合成和生物活性。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-07 DOI: 10.1016/j.bioorg.2026.110228

Xinhai Li, Bo Zhang, Xiaoting Qiu

{"title":"Biogenesis, structural diversity, biosynthesis and bioactivities of linear peptides from cyanobacteria.","authors":"Xinhai Li, Bo Zhang, Xiaoting Qiu","doi":"10.1016/j.bioorg.2026.110228","DOIUrl":"10.1016/j.bioorg.2026.110228","url":null,"abstract":"Cyanobacteria are ancient photosynthetic Gram-negative prokaryotes widely distributed in various aquatic environments, exhibiting strong adaptability and the capacity to produce a diverse range of secondary metabolites. Among these metabolites, different types of peptides, including linear and cyclic peptides, are the dominant compounds. Although a number of in-depth studies on various linear peptides originating from cyanobacteria have been published, there has not yet been a comprehensive review that systematically summarizes the diverse research on these linear peptides. This article provides a systematic overview of the research progress on 19 classes of well-studied cyanobacteria-derived linear peptides, including short chain linear peptides, fatty acid modified linear peptides, linear peptides containing specialized cyclic moieties and long chain linear peptides, focusing on their biogenesis, structural diversity, biosynthesis as well as bioactivities. These linear peptides have emerged as promising candidates for developing anticancer, anticoagulant, anti-inflammatory and antiparasitic agents due to their versatile bioactivities and structural modifiability. Integrated chemical and biosynthetic strategies offer novel approaches to enhance production efficiency and optimize the pharmacological properties of these peptides. Future research will focus on overcoming the stability limitations of these linear peptides and expanding their therapeutic applications, aiming to unlock their full potential in addressing unmet medical challenges.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110228"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From local anesthetics to antibacterial agents: design, synthesis, and activity evaluation of dyclonine quaternary ammonium salt derivatives. 从局部麻醉剂到抗菌剂：代克隆碱季铵盐衍生物的设计、合成和活性评价。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-06-20 DOI: 10.1016/j.bioorg.2026.110145

Linyuan Zhu, Yuqian Kan, Yawei Zhang, Hongji Li, Yijun Shen, En Zhang, Pingping Li, Wen Li

{"title":"From local anesthetics to antibacterial agents: design, synthesis, and activity evaluation of dyclonine quaternary ammonium salt derivatives.","authors":"Linyuan Zhu, Yuqian Kan, Yawei Zhang, Hongji Li, Yijun Shen, En Zhang, Pingping Li, Wen Li","doi":"10.1016/j.bioorg.2026.110145","DOIUrl":"10.1016/j.bioorg.2026.110145","url":null,"abstract":"The discovery of antibiotics with novel structures is a crucial strategy to combat antibiotic resistance. This study was motivated by the reported antibacterial activity of local anesthetics. Dyclonine hydrochloride, which shows the highest antibacterial activity among local anesthetics, was selected as the structural scaffold. Based on the structural characteristics of quaternary ammonium salt antibiotics, a series of dyclonine quaternary ammonium salt derivatives were designed and synthesized, and their analgesic and antibacterial activities were evaluated. The target compounds exhibited almost no analgesic effect but generally showed varying degrees of antibacterial effects against Gram-positive bacteria. Compound 17, the most potent derivative, had a minimum inhibitory concentration (MIC) of 0.5 μg/mL against S. aureus (MIC of amoxicillin against S. aureus: 2 μg/mL; MIC of dyclonine hydrochloride against S. aureus: 64 μg/mL). Further animal experiments demonstrated that compound 17 displayed excellent in vivo antibacterial activity. In addition, the preliminary action mechanism of compound 17 was studied using membrane depolarization assays, confirming that compound 17 exerted antibacterial effects by acting on bacterial cell membranes. In summary, this study identifies the β-aminoketone quaternary ammonium salt as a promising core structure for further antibiotic development.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110145"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potent and isoform-selective PARP1 degraders for the treatment of BRCA-deficient cancers. 有效的和同型选择性PARP1降解物用于治疗brca缺陷癌症。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-04 DOI: 10.1016/j.bioorg.2026.110204

Hui Sun, Yang Hu, Jiayu Xue, Rongrong Guo, Yan Liang, Bin Li, Xiaowei Xu, Jun Ren

{"title":"Potent and isoform-selective PARP1 degraders for the treatment of BRCA-deficient cancers.","authors":"Hui Sun, Yang Hu, Jiayu Xue, Rongrong Guo, Yan Liang, Bin Li, Xiaowei Xu, Jun Ren","doi":"10.1016/j.bioorg.2026.110204","DOIUrl":"10.1016/j.bioorg.2026.110204","url":null,"abstract":"PARP inhibitors leverage synthetic lethality in BRCA-mutant tumors, but resistance and PARP2- associated hematological toxicities limit their clinical utility. In this study, a series of novel PROTAC degraders utilizing the highly selective PARP1 inhibitor AZD5305 as the recruiting moiety was reported. Through linker optimization, CPP-13, a pomalidomide-based degrader with a 13-atom linker, was confirmed as the lead compound. CPP-13 exhibited potent PARP1 degradation potency (DC50 = 0.48 nM, Dmax = 90%) and robust antiproliferative activity (IC50 = 3.0 nM) in BRCA-deficient cells. Mechanistic investigations confirmed that CPP-13 functions through a CRBN-dependent ubiquitin-proteasome pathway, maintaining high isoform selectivity for PARP1 over PARP2. Furthermore, CPP-13 treatment was associated with γH2AX accumulation and selective growth inhibition in BRCA-deficient breast and pancreatic cancer models. Overall, CPP-13 serves as a valuable chemical tool and demonstrates the feasibility of selective PARP1 degradation using an AZD5305-based PROTAC strategy. Further optimization will be required to improve its pharmacokinetic properties and enable in vivo efficacy evaluation.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110204"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lead-guided prodrug development of small molecules as GLP-1R agonists. 小分子GLP-1R激动剂的先导药物开发。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-04 DOI: 10.1016/j.bioorg.2026.110210

Hannah Lentschat, Habiba G Aboelfotouh, Peter Nabil, Mennatallah Abdallah, Hend Khalifa, Jan Stichel, Mohammad Abdel-Halim, Ashraf H Abadi, Annette G Beck-Sickinger

{"title":"Lead-guided prodrug development of small molecules as GLP-1R agonists.","authors":"Hannah Lentschat, Habiba G Aboelfotouh, Peter Nabil, Mennatallah Abdallah, Hend Khalifa, Jan Stichel, Mohammad Abdel-Halim, Ashraf H Abadi, Annette G Beck-Sickinger","doi":"10.1016/j.bioorg.2026.110210","DOIUrl":"10.1016/j.bioorg.2026.110210","url":null,"abstract":"The glucagon-like peptide-1 receptor (GLP-1R) is a well-established target for treating obesity and T2DM. To date almost all approved therapies targeting this receptor are peptide-based. The small-molecule GLP-1R agonist danuglipron, developed by Pfizer, demonstrated strong GLP-1 agonistic properties, reductions in body weight and improved glycemic control. Yet, its short duration of action, gastrointestinal side effects, and a potential case of drug-induced liver disease led to discontinuation in clinical trials. In this study, we designed and synthesized a series of acid and ester analogs of danuglipron, incorporating diverse substitution patterns and deliberate modifications, including variable substitutions and key moiety replacements. The corresponding acid forms retained activity comparable to the lead compound and the peptide drug tirzepatide. Notably, the ester compound 4 exhibited a controlled and sustained conversion to its active metabolite 4a in human plasma, as confirmed by mass spectrometry and in vitro GLP-1R activity assays. These findings suggest that the ester derivatives might represent a potential approach for modulating the pharmacokinetic properties of these compounds, and the resulting prodrugs could potentially provide more sustained systemic exposure and possibly offer safety-related advantages; however, these hypotheses require further validation through appropriate in vivo pharmacokinetic and toxicological studies.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110210"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rationally designed phytochemical-derived carbamate hybrids unveiling potent inhibition of cholinesterase and amyloid-β peptides. 合理设计植物化学衍生的氨基甲酸酯杂交种揭示了胆碱酯酶和淀粉样β肽的有效抑制作用。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-10 DOI: 10.1016/j.bioorg.2026.110242

Aruna Ghose, Sudhir Kumar Paidesetty, Shakti Ketan Prusty, Bhabani Sankar Satapathy, Preetesh Kumar Panda, Kakarla Pakeeraiah, Abhishek Mishra, Rambabu Dandela

{"title":"Rationally designed phytochemical-derived carbamate hybrids unveiling potent inhibition of cholinesterase and amyloid-β peptides.","authors":"Aruna Ghose, Sudhir Kumar Paidesetty, Shakti Ketan Prusty, Bhabani Sankar Satapathy, Preetesh Kumar Panda, Kakarla Pakeeraiah, Abhishek Mishra, Rambabu Dandela","doi":"10.1016/j.bioorg.2026.110242","DOIUrl":"10.1016/j.bioorg.2026.110242","url":null,"abstract":"Alzheimer's disease (AD) is most likely to be caused by the accumulation of Aβ and dysfunction of the cholinergic pathology. Oxidative damage, alterations of brain glucose metabolism, and cognitive impairment are all demonstrated in the STZ models. In order to overcome such effects, a new set of phenolic-carbamate conjugates (5a-5h) was synthesized, and their structures were elucidated using FTIR, UV, and NMR spectroscopy. The in silico studies confirmed excellent binding capabilities against AChE and Aβ targets. In vitro antioxidant assays depicted a significant free radical scavenging ability, with compound 5c exhibiting the enhanced effect. Cell line study with SH-SY5Y and PC12 cells showed greater % cell viability. AChE activity demonstrated compound 5c has significant effectiveness (IC50 = 1.98 uM). Neurobehavioral activity showed an improvement in learning and memory during behavioural assessments. In vivo antioxidant study showed greater scavenging activity (SOD, CAT, GSH), reduced of oxidative stress (MDA, NO), and the improvement in total antioxidant activity. Overall, the compound 5c has demonstrated significant results comprising decreased cholinesterase and Aβ inhibition deciphering enhanced cholinergic restoration. Hippocampal integrity was preserved, as it was confirmed by histopathological examination. It concludes that bromo-vanillyl carbamate derivative 5c (30 mg/kg) has potent antioxidant, anti-amyloid, and neuroprotective characteristics, rendering it a promising multitarget lead that warrants further investigation for the treatment of AD.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110242"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Virtual screening-guided repurposing of fluorescent probes to detect EGFR expression in renal cells. 虚拟筛选引导下的荧光探针重新用于检测肾细胞中EGFR的表达。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-10 DOI: 10.1016/j.bioorg.2026.110203

Giovanni Graziano, Daniela Trisciuzzi, Marialessandra Contino, Alessandra Stasi, Antonio Laghezza, Maria Teresa Cimmarusti, Monica Campioni, Mariachiara Mammone, Annalisa Fanizzi, Pasquale Degennaro, Nicola Mastrofilippo, Marco Fiorentino, Paola Pontrelli, Angela Stefanachi, Nicola Antonio Colabufo, Loreto Gesualdo, Orazio Nicolotti, Francesco Leonetti

{"title":"Virtual screening-guided repurposing of fluorescent probes to detect EGFR expression in renal cells.","authors":"Giovanni Graziano, Daniela Trisciuzzi, Marialessandra Contino, Alessandra Stasi, Antonio Laghezza, Maria Teresa Cimmarusti, Monica Campioni, Mariachiara Mammone, Annalisa Fanizzi, Pasquale Degennaro, Nicola Mastrofilippo, Marco Fiorentino, Paola Pontrelli, Angela Stefanachi, Nicola Antonio Colabufo, Loreto Gesualdo, Orazio Nicolotti, Francesco Leonetti","doi":"10.1016/j.bioorg.2026.110203","DOIUrl":"10.1016/j.bioorg.2026.110203","url":null,"abstract":"Epidermal Growth Factor Receptor (EGFR) signalling plays a key role in the progression of chronic kidney disease (CKD), as its persistent activation promotes inflammation, fibrosis, and tubular cell proliferation. Aberrant EGFR expression and overactivation have therefore been associated with renal injury and disease progression, making it a relevant biomarker and potential therapeutic target in CKD. Our goal was to repurpose known fluorescent ligands, originally developed for other targets, to study EGFR expression at the kidney cell membrane in healthy and diseased conditions, providing a potential tool for disease detection and staging. Drug repurposing leverages existing pharmacokinetic and safety data, reducing time and costs, and can transform off-target effects into new applications through structure-based and AI-driven approaches. We built a database of 47 commercially available fluorescent ligands with fully disclosed structures and screened them by molecular docking against EGFR. Two promising candidates were identified and validated through preliminary kinase inhibition assays. Their performance was then evaluated in three cell lines with different EGFR expression levels (RCC, HK-2, and EGFR-negative EA.hy926). Notably, the harmonic integration of in silico and experimental approaches proved effective in the rational repurposing of two fluorescent organic ligands as probes for the detection of EGFR overexpression in CKD.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110203"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced oral absorption and anti-colorectal cancer efficacy of trifluridine by interfering with both TPase and UPase. 通过干扰TPase和UPase增强三氟吡啶的口服吸收和抗结直肠癌疗效。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-08 DOI: 10.1016/j.bioorg.2026.110237

Shulin Wan, Xinyi Fan, Peng Jin, Menghao Wei, Qianzhan Yang, Yinglan Yu, Hao Shao, Riyanto Teguh Widodo, Yaguang Wu, Lei Luo

{"title":"Enhanced oral absorption and anti-colorectal cancer efficacy of trifluridine by interfering with both TPase and UPase.","authors":"Shulin Wan, Xinyi Fan, Peng Jin, Menghao Wei, Qianzhan Yang, Yinglan Yu, Hao Shao, Riyanto Teguh Widodo, Yaguang Wu, Lei Luo","doi":"10.1016/j.bioorg.2026.110237","DOIUrl":"10.1016/j.bioorg.2026.110237","url":null,"abstract":"Oral nucleoside anticancer drugs are frequently limited by rapid enzymatic degradation, leading to inadequate systemic exposure and poor therapeutic efficacy. Trifluridine (FTD), a thymidine analogue used for metastatic colorectal cancer (CRC), is rapidly inactivated by thymidine phosphorylase (TPase) and uridine phosphorylase (UPase). Although the approved trifluridine/tipiracil (FTD/TPI) therapy protects FTD from TPase-mediated degradation, UPase remains insufficiently controlled. Uridine triacetate (TAU), a uridine prodrug, is used to sustain systemic uridine exposure and attenuate UPase-mediated FTD degradation. Here, we developed a dual-enzyme metabolic protection strategy for enhancing FTD exposure through TAU-mediated UPase and TPI-mediated TPase. The results indicated that uridine and FTD bound to the same UPase site, and elevated uridine exposure significantly increased oral FTD absorption. Among different TAU particle sizes, 200 μm slowed gastrointestinal release, generated maximal uridine exposure, and increased FTD absorption by 4.0-fold and 1.6-fold compared with FTD alone and FTD/TPI, respectively. Further, the combination of TPI and TAU achieved dual protection against UPase and TPase, maximized FTD exposure, and demonstrated favorable short-term safety. Notably, the half-dose FTD in combination with TAU and TPI achieved a systemic exposure comparable to that of full-dose FTD/TPI, indicating a potential dose-sparing effect. In colorectal cancer models, the combination markedly promoted anti-tumor efficacy through suppression of cell proliferation and induction of cell apoptosis. These findings establish a prodrug-enabled metabolic protection strategy for improving oral pharmacokinetics and therapeutic efficacy of metabolically vulnerable nucleoside anticancer drugs.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110237"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Turmeric-derived mesoporous carbon as a bioactive material: In vitro anticancer, antidiabetic, and anti-inflammatory evaluation. 姜黄衍生的介孔碳作为一种生物活性材料：体外抗癌、降糖和抗炎评价。

IF 5.1 2区医学

Bioorganic Chemistry Pub Date : 2026-09-15 Epub Date: 2026-07-10 DOI: 10.1016/j.bioorg.2026.110223

K Saravanan, P Seenuvasakumaran, A Ubaithulla Baig, A Gomathiyalini, M Ayyanar, R Balaji, Sharada H Sharma, A Baskaran, N Jabena Begum

{"title":"Turmeric-derived mesoporous carbon as a bioactive material: In vitro anticancer, antidiabetic, and anti-inflammatory evaluation.","authors":"K Saravanan, P Seenuvasakumaran, A Ubaithulla Baig, A Gomathiyalini, M Ayyanar, R Balaji, Sharada H Sharma, A Baskaran, N Jabena Begum","doi":"10.1016/j.bioorg.2026.110223","DOIUrl":"10.1016/j.bioorg.2026.110223","url":null,"abstract":"Breast cancer, diabetes, and chronic inflammatory diseases are major global health challenges, which call for the development of effective biomaterials with potential biomedical applications. In this work, Curcuma longa based mesoporous carbon material (CCL) has been successfully prepared through NaOH-assisted chemical activation and examined in depth for physicochemical and biomedical properties. Results of this experiment indicate successful synthesis of mesoporous carbon material with an average pore size, surface area, and stability temperature of 3.80 nm, 1394.5 m2/g, and 800 °C, respectively. The CCL showed considerable antioxidant activity with an IC₅₀ value of 76.25 ± 2.13 and 68.58 ± 2.12 μg/mL in the DPPH and superoxide radical scavenging assays, respectively. Notable antidiabetic effect have also been found with α-amylase and α-glucosidase inhibitory activities, which described an IC₅₀ value of 89.86 ± 3.25 and 98.65 ± 1.97 μg/mL, respectively. Strong anti-inflammatory capacity has been found in protein-denaturing assay with an IC₅₀ of 72.49 ± 0.62 μg/mL. The material showed high anticancer activity against triple-negative breast cancer cells (MDA-MB-231) with an IC₅₀ value of 24.97 μg/mL and showed apoptosis. The comparative analysis with various previous reports on turmeric-derived materials represents significantly high anticancer activity in this formulation. The synthesized material exhibited enhanced anticancer activity compared with previously reported turmeric-derived materials. Together with its observed antidiabetic and anti-inflammatory activities, these results highlight its potential as a bioactive material for further in-vitro and in-vivo studies.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"180 ","pages":"110223"},"PeriodicalIF":5.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0