Bioorganic Chemistry最新文献

{"title":"Design, synthesis and evaluation of NBP/borneol hybrids as neuroprotective agents for the treatment of ischemic stroke.","authors":"Xiaolin Wang, Guangyu Li, Haoyue Shen, Chenwei Zuo, Qing Wu, Hai Shang, Yu Tian","doi":"10.1016/j.bioorg.2025.109056","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109056","url":null,"abstract":"<p><p>The pathogenesis of cerebral ischemia is a highly complex biochemical process, mainly caused by cerebral vascular occlusion or rupture, which results in the interruption of blood flow and ischemic injury to brain tissue. Based on 3-n-Butylphthalide (NBP), a listed drug with approved neuroprotective properties, a series of NBP/Borneol hybrids were designed, synthesized and evaluated for their biological activities in vitro. Most of these compounds exhibited potent neuroprotection with low cytotoxicity, among all derivatives, L-NRB and S6b exhibited significantly improved cell viabilities compared to NBP in OGD/R model and glutamate induced model using HT22 cells. Further biological activity studies revealed that compounds L-NRB, S6b inhibit LDH release and may exert anti-cerebral ischemia activities by resisting oxidative stress and reducing apoptosis. In addition, L-NRB, S6b could regulate the levels of apoptosis pathway-related proteins Caspase 3, Bcl-2 and Bax. Notably, S6b reduced cerebral thrombosis in the ponatinib-induced zebrafish model. In conclusion, this work designed, synthesized and evaluated a novel series of NBP derivatives with neuroprotective activity and provides a reference for the design of other potential compounds for the treatment of ischemic stroke.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109056"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249000","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}

{"title":"Recent advances in the Total synthesis and structural modification of Ecteinascidin-743.","authors":"Yang Yang, Ju Guo, Yancheng Liu","doi":"10.1016/j.bioorg.2025.109047","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109047","url":null,"abstract":"<p><p>Ecteinascidin 743 (ET-743), commercially known as Trabectedin, stands as a pioneering marine-derived antitumor agent and a flagship member of the tetrahydroisoquinoline (THIQ) alkaloid family. As the first marine-based drug to achieve clinical approval, ET-743 was authorized by the European Union in 2007 and the U.S. Food and Drug Administration (FDA) in 2015 for the treatment of advanced soft tissue sarcomas, and it is now employed in nearly 80 countries and regions globally. The molecular architecture of ET-743 is distinguished by a highly intricate pentacyclic scaffold, comprising two tetrahydroisoquinoline subunits fused through a central piperazine ring and further embellished with a tetrahydroisoquinoline side chain linked via a thioether bridge. This structural complexity not only underpins its potent biological activity but also presents significant synthetic challenges, rendering ET-743 a focal point of interest in the realm of natural product synthesis. Over the past decades, considerable efforts have been devoted to the total synthesis and structural modification of ET-743, yielding innovative synthetic strategies and analogs with enhanced pharmacological profiles. This review provides a comprehensive analysis of recent advancements in the total synthesis and structural optimization of ET-743, emphasizing key methodologies, synthetic breakthroughs, and structure-activity relationship (SAR) insights. By consolidating these developments, this work aims to furnish a robust scientific foundation for future research endeavors aimed at harnessing the therapeutic potential of tetrahydroisoquinoline-based natural products.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109047"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243383","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}

{"title":"Isolation and identification of Garciyunnanensisin A-O from Garcinia yunnanensis: a study on its antibacterial activity and mechanism against Staphylococcus aureus.","authors":"Peng-Xue Ji, Zhi-Yuan Li, Sheng-Nan Yang, Si-Han Wang, Yun Gao, Zi-Feng Guo, Jing-Ming Jia, Shao-Hui Huang, Zhen-Zhong Wang, An-Hua Wang","doi":"10.1016/j.bioorg.2025.109023","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109023","url":null,"abstract":"<p><p>Staphylococcus aureus has a strong biofilm-forming ability that protects it from the external environment, making it difficult to remove during food processing and storage, thereby increasing the incidence of foodborne illness. In order to improve food safety and protect human health, it is important to find safe and effective antimicrobial agents. In this study, a total of 20 compounds (1-20), including 15 new compounds (1-15), were isolated from Garcinia yunnanensis and elucidated by Nuclear Magnetic Resonance (NMR) data analysis, calculation of optical rotation values, and Electronic Circular Dichroism (ECD) spectra. Compound 1, a rare caged polycyclic polyprenylated acylphloroglucinol, demonstrated significant antibacterial activity against S. aureus with a minimum inhibitory concentration (MIC) of 6.25 μg/mL and showed rapid bactericidal effects at high concentrations. In addition, 1 inhibited S. aureus biofilm formation by reducing bacterial metabolism, decreasing bacterial viability, inhibiting bacterial surface hydrophobicity and adhesion, and modulating the synthesis and secretion of extracellular polysaccharides, DNA, and proteins. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) also further confirmed that 1 significantly inhibited biofilm formation. In conclusion, 1 not only has excellent antibacterial and biofilm inhibitory properties, but also exhibits low toxicity, making it a promising candidate for development as a food-grade bacterial biofilm inhibitor.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109023"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243438","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}

{"title":"Novel 2,6-Bis(indolyl/ 5-bromoindolyl)dihydropyridine/pyridine hybrids as potential anti-tumor agents: Design, one-pot Green synthesis, molecular docking, and cytotoxicity evaluation","authors":"Norhan K. Hasan ,&nbsp;Zeinab Mahmoud ,&nbsp;Manal M. Kandeel ,&nbsp;Ahmed A.F. Soliman ,&nbsp;Eman A. El-Khouly","doi":"10.1016/j.bioorg.2025.109058","DOIUrl":"10.1016/j.bioorg.2025.109058","url":null,"abstract":"&lt;div&gt;&lt;div&gt;This work presents seventeen new bis(indolyl/5-bromoindolyl)dihydropyridine and bis(indolyl/5-bromoindolyl)pyridine derivatives synthesized using an eco-friendly, solvent-free, and catalyst-free protocol. The reaction occurred between different aldehydes and 3-(1&lt;em&gt;H&lt;/em&gt;-indol-3-yl)-3-oxopropanenitrile (&lt;strong&gt;1a&lt;/strong&gt;), or 3-(5-bromo-1&lt;em&gt;H&lt;/em&gt;-indol-3-yl)-3-oxopropanenitrile (&lt;strong&gt;1b&lt;/strong&gt;), or 1-(1&lt;em&gt;H&lt;/em&gt;-indol-3-yl)ethan-1-one (&lt;strong&gt;4&lt;/strong&gt;) in the presence of ammonium acetate &lt;em&gt;via&lt;/em&gt; one-pot reaction cyclization. The structures of the synthesized compounds were confirmed by IR, &lt;sup&gt;1&lt;/sup&gt;H NMR, &lt;sup&gt;13&lt;/sup&gt;C NMR, and elemental analysis. The synthesized compounds were evaluated for their anticancer activity against the colon (HCT-116) cancer cell line, the breast (MCF-7) cancer cell line, and normal epithelial cells (RPE-1) using the MTT assay. Compounds &lt;strong&gt;2a&lt;/strong&gt;, &lt;strong&gt;2b&lt;/strong&gt;, &lt;strong&gt;2c&lt;/strong&gt;, &lt;strong&gt;2f&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;g&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;h&lt;/strong&gt;, &lt;strong&gt;2i&lt;/strong&gt;, &lt;strong&gt;2j&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;k&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;l&lt;/strong&gt;, and &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;m&lt;/strong&gt; exhibited more antiproliferative activity (IC&lt;sub&gt;50&lt;/sub&gt; values of 1.07–6.9 μM against the MCF-7 cell line and IC&lt;sub&gt;50&lt;/sub&gt; values ranging from 2.69 to 6.37 μM against the HCT-116 cell line) than that of doxorubicin against the two tested cell lines (IC&lt;sub&gt;50&lt;/sub&gt; = 9 μM and 7.1 μM against MCF-7 and HCT-116, respectively). Compounds &lt;strong&gt;2a&lt;/strong&gt;, &lt;strong&gt;2b&lt;/strong&gt;, &lt;strong&gt;2c&lt;/strong&gt;, &lt;strong&gt;2e&lt;/strong&gt;, &lt;strong&gt;2f&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt; &lt;strong&gt;g&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;h&lt;/strong&gt;, &lt;strong&gt;2i&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;k&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;l&lt;/strong&gt;, &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;m&lt;/strong&gt;, and &lt;strong&gt;5&lt;/strong&gt; were found to be more selective against both cell lines than normal epithelial cells (RPE-1). Compounds &lt;strong&gt;2b, 2f, 2i, 2j, 2&lt;/strong&gt;&lt;strong&gt;k,&lt;/strong&gt; and &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;l,&lt;/strong&gt; in addition to doxorubicin&lt;strong&gt;,&lt;/strong&gt; were further subjected to an &lt;em&gt;in vitro&lt;/em&gt; VEGFR-1 inhibition assay in the MCF-7 and HCT-116 cell lines. Compounds &lt;strong&gt;2j&lt;/strong&gt; and &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;l&lt;/strong&gt; demonstrated excellent VEGFR-1 inhibitory activity in both cell lines compared to doxorubicin (% inhibition in HCT-116 = 89.23 %, 88.9 %, and 53.85 %, respectively, and % inhibition in MCF-7 = 93.16 %, 94.89 %, and 86.9 %, correspondingly). Cell cycle analysis was performed for the most potent derivatives, compounds &lt;strong&gt;2j&lt;/strong&gt; and &lt;strong&gt;2&lt;/strong&gt; &lt;strong&gt;l&lt;/strong&gt;, which arrested MCF-7 cells at the G&lt;sub&gt;0&lt;/sub&gt;/G&lt;sub&gt;1&lt;/sub&gt; phase with high percentages (94.18 % and 86.80 %, respectively). The expression levels of the caspase-3 gene induced by compound &lt;strong&gt;2&lt;/strong&gt;&lt;strong&gt;l&lt;/strong&gt; treatment were statistically comparable to those of do","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"166 ","pages":"Article 109058"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265749","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}

{"title":"Small-molecule inhibitors of GSK3β: Therapeutic potential and structure-activity relationship in multiple systems.","authors":"Jiale Wang, Dan Wang, Fanfei Liu, Yan Ji, Xuling Peng, Gen Li","doi":"10.1016/j.bioorg.2025.109053","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109053","url":null,"abstract":"<p><p>Protein kinases (PK) are a class of enzymes that phosphorylate protein molecules and play crucial roles in various biological processes, including cell proliferation, apoptosis, cell cycle regulation, differentiation, and signalling pathways. As essential components of the human body, they have become a major focus in drug development. Consequently, protein kinase inhibitors have emerged as a prominent area of clinical medicine. In recent years, small molecule inhibitors targeting glycogen synthase kinase-3 (GSK3), a representative protein kinase, have been increasingly used in clinical settings. This review comprehensively summarises 26 GSK3β small molecule inhibitors, categorizing them by their therapeutic applications across nine major systemic diseases. It also summarises the structure-activity relationships of several common compounds and examines, through molecular docking, the protein-binding capabilities of highly selective and specific inhibitors, many of which are already in clinical use or nearing clinical entry. By proposing promising research directions and establishing a solid foundation, this work paves the way for developing GSK3β small molecule inhibitors tailored to diverse diseases.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109053"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256959","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}

{"title":"Unraveling the mechanisms of ubiquitin-specific proteases in hepatocellular carcinoma: A focus on inhibitors.","authors":"Yaojiang Xu, Jiayuan Ye","doi":"10.1016/j.bioorg.2025.109049","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109049","url":null,"abstract":"<p><p>Due to heterogeneity and the development of drug resistance, Hepatocellular carcinoma (HCC) patients still benefit minimally from current treatment methods. In recent years, an increasing number of studies have reported the presence of abnormal ubiquitination modifications in HCC. Therefore, exploring the underlying regulatory mechanisms and developing effective interventions hold the promise of providing new treatment options for HCC patients. This article focuses on the deubiquitinating enzymes (DUB) that play a promoting role in the occurrence and development of HCC, emphasizing their mechanisms of action and related small molecule interventions, with the aim of providing new strategies for the treatment of HCC.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109049"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211147","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}

{"title":"Design, synthesis, and biological evaluation of death-associated protein kinase 1 PROTACs.","authors":"Xueyin Wu, Ruomeng Li, Wujin Tian, Jing Yao, Dongmei Chen, Tae Ho Lee, Yang Liu","doi":"10.1016/j.bioorg.2025.109044","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109044","url":null,"abstract":"<p><p>Death-associated protein kinase 1 (DAPK1) serves as a crucial regulator of both autophagy and apoptosis. DAPK1 has been closely linked to cancer and various neurodegenerative diseases. Neurodegenerative disorders are chronic and progressive conditions characterized by the gradual loss of neuronal function and structure. Despite ongoing research, no effective cure currently exists, and further studies are needed. The emerging PROteolysis TArgeting Chimeras (PROTACs) strategy, characterized by high potency and broad target coverage, may represent a promising avenue for therapeutic development. Here we describe the design, synthesis, and biological evaluation of first-in-class PROTACs targeting DAPK1. The compound with the most promising results, CP1, can achieve sustained and effective degradation of DAPK1 at a relatively low concentration (DC₅₀ = 0.1196 μM). Overall, our compound CP1 demonstrated strong efficacy in degrading DAPK1 and shows potential for treating neuronal cell death.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109044"},"PeriodicalIF":4.7,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205097","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}

{"title":"Development of APOBEC3B inhibitors: Recent advances and perspectives.","authors":"Wenjie Zhang, Yuhang Wang, Cheng Jiang","doi":"10.1016/j.bioorg.2025.109042","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109042","url":null,"abstract":"<p><p>The apolipoprotein B mRNA editing catalytic polypeptide-like 3B (A3B) is a member of the cytidine deaminase A3 family, which plays a crucial role in the viral immune process. As a cytosine deaminase, A3B is a major contributor to tumor-associated mutations. Numerous studies have shown that A3B is aberrantly expressed in a variety of tumor cells, which promotes tumor growth, migration, and drug resistance. Hence, A3B is deemed a promising candidate for potential therapeutic interventions against tumor resistance. Presently, although research on A3B inhibitors is still in its early stages, various selective inhibitors have already been reported. Notably, oligonucleotide and allosteric inhibitors have more desirable effects. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of A3B. Subsequently, we summarize the literature covering various A3B inhibitors and discuss their design requirements and modes of action.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109042"},"PeriodicalIF":4.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197528","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}

{"title":"A comprehensive review of targeting sterol 14α-demethylase and sterol C-24 methyl transferase, two pivotal proteins in Leishmania, as compelling therapeutic targets.","authors":"Diksha Kumari, Somdutt Mujwar, Kuljit Singh","doi":"10.1016/j.bioorg.2025.109046","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109046","url":null,"abstract":"<p><p>Leishmaniasis, a neglected tropical disease, poses a significant global health challenge mainly in tropical and subtropical areas. The limited treatment alternatives, coupled with significant associated toxicity, necessitate the requirement to identify new chemical scaffolds with reduced toxicity and improved efficacy. The two essential enzymes of the sterol biosynthetic pathway, Sterol C-24 methyl transferase (SMT) and Sterol 14α-demethylase (SDM), hold great promise as plausible drug targets due to their essentiality for parasite survival and virulence, along with exhibiting minimal homology with human counterparts. The present review discusses the importance of targeting leishmanial SDM and SMT proteins in the perquisite for anti-leishmanial drug discovery. We have performed a comprehensive search using various databases and created a small-molecule sterol inhibitor library, and by utilizing computational biology approaches, we tried to meticulously understand enzyme-inhibitor interactions of the library molecules with the leishmanial SMT and SDM proteins. Information pertaining to the chemical structure of the inhibitors, binding affinities, and interacting residues with both the proteins that drive their mode of action towards them has been elucidated. Thus, this review addresses inclusive information on Leishmanial SMT and SDM proteins, which can aid in unraveling new molecules to fight against the deadly parasitic infection by leveraging computational tools.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109046"},"PeriodicalIF":4.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197710","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}

{"title":"Recent progress in topoisomerase inhibitors as anticancer agents: Research and design strategies for Topo I and II inhibitors via structural optimization.","authors":"Guanghuan Shen, Shihao Li, Yu Zhu, Zheng Xu, Xuan Liu, Chunyan Lv, Zhihua Xing, Linlin Cui, Wenlan Li","doi":"10.1016/j.bioorg.2025.109040","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109040","url":null,"abstract":"<p><p>Topoisomerase (Topo) is a crucial class of enzymes that play significant roles in DNA replication, transcription, and repair. Epidemiological research has highlighted the necessity of topoisomerase for the proliferation and genomic stability of tumor cells. Currently, the main topoisomerase inhibitors used in cancer therapy are toxins and catalytic inhibitors that target topoisomerase I (Topo I) and topoisomerase II (Topo II). These inhibitors hinder tumor cell proliferation by disrupting DNA topology regulation. However, prolonged use of these traditional drugs can lead to issues such as drug resistance, cardiotoxicity, and myelosuppression. Thus, there is a pressing need to develop innovative topoisomerase inhibitors with high efficacy and low toxicity. This review systematically summarizes and analyzes the structural and optimization advances of Topo I and II inhibitors over the past five years, with particular attention to catalytic inhibitors and multitarget agents, aiming to provide new perspectives for the development of safer and more effective small-molecule topoisomerase inhibitors for cancer therapy.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109040"},"PeriodicalIF":4.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205184","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}