Bioorganic & Medicinal Chemistry最新文献_第7页

Linkers for effective peptide-drug conjugates 有效肽-药物偶联物的连接物

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-12-02 DOI: 10.1016/j.bmc.2025.118510

Mohamad Fajar , Rani Maharani , Unang Supratman

Despite their notable anticancer efficacy, many established cancer drugs such as Doxorubicin, camptothecin, paclitaxel, gemcitabine, and methotrexate exhibit limited selectivity to target cancer cells over normal cells. Because these conventional chemotherapeutic agents frequently impact both healthy and cancerous cells, they have high side effects constraining their overall therapeutic index. The challenge arises from their inability to selectively target tumor cells with cytotoxic effects while sparing the surrounding healthy tissues. In response to these limitations, peptide-drug conjugate (PDC) strategies have emerged as an innovative category of targeted therapies designed to improve drug delivery and reduce off-target effects. PDCs utilize the specificity of peptides to deliver cytotoxic agents more accurately to cancer cells, thereby improving therapeutic outcomes and reducing adverse side reactions. PDCs employ peptides that selectively bind to overexpressed receptors on tumor cells, enabling targeted therapy with minimal side effects in cancer patients. To successfully synthesize peptide-drug conjugates, it is essential to have a solid understanding of the active site of the drug, recognition site of the peptide, and where the drug will be release inside the tumor cells. The linker between the drug and the peptide plays a critical role in the stability and release profile of the conjugates, which influence how effectively the drug reaches its target site of action and how it is released within the tumor cells. The choice of linker can determine the pharmacokinetics and bioavailability profiles of PDCs, making it a vital aspect of their design. The review is aimed at providing a comprehensive review of various drug-peptide conjugates with a particular emphasis on the linkers and PDC synthetic methods. Here, we described the advancements PDC chemistries and potential future research areas in drug delivery systems. In addition, we hope to contribute valuable insights into optimizing PDC design for enhanced efficacy in cancer therapy.

尽管它们具有显著的抗癌功效，但许多已建立的抗癌药物，如阿霉素、喜树碱、紫杉醇、吉西他滨和甲氨蝶呤，对癌细胞的选择性比对正常细胞的选择性有限。由于这些常规化疗药物经常影响健康细胞和癌细胞，它们有很高的副作用，限制了它们的整体治疗指数。挑战在于它们无法选择性地靶向具有细胞毒性作用的肿瘤细胞，同时保留周围的健康组织。针对这些局限性，肽-药物偶联（PDC）策略已成为一种创新的靶向治疗类别，旨在改善药物传递和减少脱靶效应。PDCs利用多肽的特异性更准确地向癌细胞递送细胞毒性药物，从而改善治疗效果并减少不良副作用。PDCs使用选择性结合肿瘤细胞上过表达受体的肽，使癌症患者能够以最小的副作用进行靶向治疗。为了成功地合成肽-药物偶联物，必须对药物的活性位点、肽的识别位点以及药物在肿瘤细胞内的释放位置有深入的了解。药物和肽之间的连接物在缀合物的稳定性和释放特征中起着关键作用，这影响药物如何有效地到达其作用靶点以及如何在肿瘤细胞内释放。连接体的选择可以决定PDCs的药代动力学和生物利用度，使其成为其设计的重要方面。本文综述了各种药物-肽偶联物的研究进展，重点介绍了它们的连接体和PDC的合成方法。在这里，我们描述了PDC化学的进展和潜在的未来研究领域在药物输送系统。此外，我们希望为优化PDC设计以提高癌症治疗效果提供有价值的见解。

{"title":"Linkers for effective peptide-drug conjugates","authors":"Mohamad Fajar , Rani Maharani , Unang Supratman","doi":"10.1016/j.bmc.2025.118510","DOIUrl":"10.1016/j.bmc.2025.118510","url":null,"abstract":"<div><div>Despite their notable anticancer efficacy, many established cancer drugs such as Doxorubicin, camptothecin, paclitaxel, gemcitabine, and methotrexate exhibit limited selectivity to target cancer cells over normal cells. Because these conventional chemotherapeutic agents frequently impact both healthy and cancerous cells, they have high side effects constraining their overall therapeutic index. The challenge arises from their inability to selectively target tumor cells with cytotoxic effects while sparing the surrounding healthy tissues. In response to these limitations, peptide-drug conjugate (PDC) strategies have emerged as an innovative category of targeted therapies designed to improve drug delivery and reduce off-target effects. PDCs utilize the specificity of peptides to deliver cytotoxic agents more accurately to cancer cells, thereby improving therapeutic outcomes and reducing adverse side reactions. PDCs employ peptides that selectively bind to overexpressed receptors on tumor cells, enabling targeted therapy with minimal side effects in cancer patients. To successfully synthesize peptide-drug conjugates, it is essential to have a solid understanding of the active site of the drug, recognition site of the peptide, and where the drug will be release inside the tumor cells. The linker between the drug and the peptide plays a critical role in the stability and release profile of the conjugates, which influence how effectively the drug reaches its target site of action and how it is released within the tumor cells. The choice of linker can determine the pharmacokinetics and bioavailability profiles of PDCs, making it a vital aspect of their design. The review is aimed at providing a comprehensive review of various drug-peptide conjugates with a particular emphasis on the linkers and PDC synthetic methods. Here, we described the advancements PDC chemistries and potential future research areas in drug delivery systems. In addition, we hope to contribute valuable insights into optimizing PDC design for enhanced efficacy in cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118510"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Novel oxadiazole analogs as anticancer agents: Design, synthesis, in vitro and in vivo biological evaluation, and computer studies of sphingosine kinase inhibitors 新型恶二唑类抗癌药物：鞘氨醇激酶抑制剂的设计、合成、体外和体内生物学评价及计算机研究

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-11-14 DOI: 10.1016/j.bmc.2025.118487

Fuxun Huang , Xinmei Yang , Haiyang Wang , Xiujuan Shi , Xiaodong Zhao , Junru Liu , Yueyang Sun , Xingbo Song , Tong Li , Zhaoyang Li , Xi Qiu , Jingtong Feng , Yuanyuan Liu , Yuqi Gao , Yanling Mu , Zhengguo Cui , Peng Zhan , Bo Liu

Sphingosine kinases (SphKs) have emerged as novel therapeutic targets for treating cancer and inflammation via the SphK/S1P signaling pathway. However, the development of selective SphK inhibitors has been challenging because of their limited specificity. In this study, we used pharmacophore- and docking-based virtual screening to identify the lead compound DTD-8 (SphK1 IC₅₀ = 79 ± 0.73 μM) and then optimized the structure through structure-based drug design. Our newly synthesized 1,2,4-oxadiazole derivative, compound 22c, demonstrated selective inhibition against SphK2 (IC₅₀ = 2.24 ± 0.60 μM) over SphK1 (IC₅₀ = 64.20 ± 1.53 μM), representing 28-fold selectivity for SphK2. It also exhibited more potent anticancer activity against DU145 cells (IC₅₀ = 3.09 ± 0.67 μM) than cisplatin (IC₅₀ = 10.67 ± 1.00 μM) owing to its ability to induce S/G2 phase arrest and apoptosis.

In rats, Compound 22c showed favorable pharmacokinetic properties, including good metabolic stability (T₁_/₂ = 19.6 h) and high plasma exposure (AUC₀–t = 1077.40 ng h/mL), along with promising in vivo tumor growth inhibition (TGI = 65.96 %). Given its moderate oral bioavailability (F = 54.88 %) and potent anticancer effects, 22c requires further investigation. These findings provide valuable insights for developing novel SphK2-targeted anticancer agents.

sphingosin激酶（SphKs）已成为通过SphK/S1P信号通路治疗癌症和炎症的新靶点。然而，选择性SphK抑制剂的开发一直具有挑战性，因为它们的特异性有限。在本研究中，我们使用基于药效团和对接的虚拟筛选方法鉴定了先导化合物DTD-8 (SphK1 IC₅₀= 79±0.73 μM)，然后通过基于结构的药物设计对结构进行优化。我们新合成的1,2,4-二唑衍生物，化合物22c，对SphK2 （IC₅₀= 2.24±0.60 μM）的选择性抑制作用优于SphK1 (IC₅₀= 64.20±1.53 μM)，对SphK2的选择性为28倍。由于其诱导S/G2期阻滞和细胞凋亡的能力，它对DU145细胞（IC₅₀= 3.09±0.67 μM）的抗癌活性也比顺铂（IC₅₀= 10.67±1.00 μM）更强。在大鼠中，化合物22c表现出良好的药代动力学特性，包括良好的代谢稳定性（T₁/ 2 = 19.6 h）和高血浆暴露（AUC 0 -t = 1077.40 ng h/mL），以及有希望的体内肿瘤生长抑制（TGI = 65.96%）。鉴于其中等的口服生物利用度（F = 54.88%）和有效的抗癌作用，22c需要进一步的研究。这些发现为开发新的sphk2靶向抗癌药物提供了有价值的见解。

{"title":"Novel oxadiazole analogs as anticancer agents: Design, synthesis, in vitro and in vivo biological evaluation, and computer studies of sphingosine kinase inhibitors","authors":"Fuxun Huang , Xinmei Yang , Haiyang Wang , Xiujuan Shi , Xiaodong Zhao , Junru Liu , Yueyang Sun , Xingbo Song , Tong Li , Zhaoyang Li , Xi Qiu , Jingtong Feng , Yuanyuan Liu , Yuqi Gao , Yanling Mu , Zhengguo Cui , Peng Zhan , Bo Liu","doi":"10.1016/j.bmc.2025.118487","DOIUrl":"10.1016/j.bmc.2025.118487","url":null,"abstract":"<div><div>Sphingosine kinases (SphKs) have emerged as novel therapeutic targets for treating cancer and inflammation <em>via</em> the SphK/S1P signaling pathway. However, the development of selective SphK inhibitors has been challenging because of their limited specificity. In this study, we used pharmacophore- and docking-based virtual screening to identify the lead compound <strong>DTD-8</strong> (SphK1 IC₅₀ = 79 ± 0.73 μM) and then optimized the structure through structure-based drug design. Our newly synthesized 1,2,4-oxadiazole derivative, compound <strong>22c</strong>, demonstrated selective inhibition against SphK2 (IC₅₀ = 2.24 ± 0.60 μM) over SphK1 (IC₅₀ = 64.20 ± 1.53 μM), representing 28-fold selectivity for SphK2. It also exhibited more potent anticancer activity against DU145 cells (IC₅₀ = 3.09 ± 0.67 μM) than cisplatin (IC₅₀ = 10.67 ± 1.00 μM) owing to its ability to induce S/G2 phase arrest and apoptosis.</div><div>In rats, Compound <strong>22c</strong> showed favorable pharmacokinetic properties, including good metabolic stability (T₁<sub>/</sub>₂ = 19.6 h) and high plasma exposure (AUC₀–<em>t</em> = 1077.40 ng h/mL), along with promising <em>in vivo</em> tumor growth inhibition (TGI = 65.96 %). Given its moderate oral bioavailability (F = 54.88 %) and potent anticancer effects, <strong>22c</strong> requires further investigation. These findings provide valuable insights for developing novel SphK2-targeted anticancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118487"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Peptide-based approaches to quorum-sensing disruption: emerging trends and applications in antimicrobial therapy 基于多肽的群体感应中断方法：新兴趋势和抗菌治疗中的应用

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-11-23 DOI: 10.1016/j.bmc.2025.118496

Mo Ahamad Khan , Lechen Zhu , Hu Zhu

The rise of antimicrobial resistance (AMR) has outpaced the development of new antibiotics, necessitating alternative therapeutic strategies that do not rely on conventional bactericidal approaches. Quorum-sensing (QS), a bacterial communication system that regulates virulence, biofilm formation and genetic competence, has emerged as a promising non-lethal target. Peptide-based quorum-sensing inhibitors (QSIs) including antimicrobial peptides (AMPs), cyclic dipeptides, and synthetic analogs are gaining recognition for their ability to disrupt QS pathways and attenuate pathogenicity without promoting resistance. This review summarizes recent advancements in peptide-mediated QS interference, covering mechanistic insights, molecular design strategies, and application domains. Natural AMPs such as LL-37 and GH12 modulate QS by altering gene expression or blocking receptor function, while marine-derived cyclic dipeptides act as competitive inhibitors of QS receptors like LasR and CviR. Engineered peptides and peptide-nanocomposite systems have demonstrated improved stability and target specificity, particularly against multidrug-resistant pathogens. Applications span wound healing, prevention of dental biofilms, and prevention of infectious diseases development. However, challenges remain, including peptide instability, low bioavailability, off-target effects, and potential resistance development. Peptide-based QSIs represent a paradigm shift in antimicrobial therapy by disabling bacterial virulence without directly killing cells. Advances in peptide engineering, delivery systems, and synthetic biology are accelerating their clinical and environmental translation. With continued innovation and adapted regulatory frameworks, peptide-based QS inhibition may become a cornerstone of next-generation anti-virulence therapeutics.

抗菌素耐药性（AMR）的上升速度超过了新抗生素的发展速度，因此需要不依赖于传统杀菌方法的替代治疗策略。群体感应（QS）是一种调节毒力、生物膜形成和遗传能力的细菌通信系统，已成为一种有希望的非致命靶标。基于肽的群体感应抑制剂（qsi），包括抗菌肽（amp）、环二肽和合成类似物，因其破坏QS通路和在不促进耐药性的情况下减弱致病性的能力而获得认可。本文综述了肽介导的QS干扰的研究进展，包括机制、分子设计策略和应用领域。天然AMPs如LL-37和GH12通过改变基因表达或阻断受体功能来调节QS，而海洋来源的环二肽则作为LasR和CviR等QS受体的竞争性抑制剂。工程肽和肽-纳米复合系统已经证明了更好的稳定性和靶向特异性，特别是针对多药耐药病原体。应用范围包括伤口愈合、预防牙齿生物膜和预防传染病的发展。然而，挑战仍然存在，包括肽的不稳定性、低生物利用度、脱靶效应和潜在的耐药性发展。基于肽的qsi代表了抗菌治疗的范式转变，通过禁用细菌毒力而不直接杀死细胞。肽工程、传递系统和合成生物学的进步正在加速它们的临床和环境转化。随着不断的创新和适应的监管框架，基于肽的QS抑制可能成为下一代抗毒治疗的基石。

{"title":"Peptide-based approaches to quorum-sensing disruption: emerging trends and applications in antimicrobial therapy","authors":"Mo Ahamad Khan , Lechen Zhu , Hu Zhu","doi":"10.1016/j.bmc.2025.118496","DOIUrl":"10.1016/j.bmc.2025.118496","url":null,"abstract":"<div><div>The rise of antimicrobial resistance (AMR) has outpaced the development of new antibiotics, necessitating alternative therapeutic strategies that do not rely on conventional bactericidal approaches<em>.</em> Quorum-sensing (QS), a bacterial communication system that regulates virulence, biofilm formation and genetic competence, has emerged as a promising non-lethal target. Peptide-based quorum-sensing inhibitors (QSIs) including antimicrobial peptides (AMPs), cyclic dipeptides, and synthetic analogs are gaining recognition for their ability to disrupt QS pathways and attenuate pathogenicity without promoting resistance. This review summarizes recent advancements in peptide-mediated QS interference, covering mechanistic insights, molecular design strategies, and application domains. Natural AMPs such as LL-37 and GH12 modulate QS by altering gene expression or blocking receptor function, while marine-derived cyclic dipeptides act as competitive inhibitors of QS receptors like <em>LasR and CviR.</em> Engineered peptides and peptide-nanocomposite systems have demonstrated improved stability and target specificity, particularly against multidrug-resistant pathogens. Applications span wound healing, prevention of dental biofilms, and prevention of infectious diseases development. However, challenges remain, including peptide instability, low bioavailability, off-target effects, and potential resistance development. Peptide-based QSIs represent a paradigm shift in antimicrobial therapy by disabling bacterial virulence without directly killing cells. Advances in peptide engineering, delivery systems, and synthetic biology are accelerating their clinical and environmental translation. With continued innovation and adapted regulatory frameworks, peptide-based QS inhibition may become a cornerstone of next-generation anti-virulence therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118496"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Corrigendum to “Redox-cleavable disulfide linker enhances siRNA delivery by prodrug-type bifunctional cell-penetrating peptide” [Bioorg. Med. Chem. 130 (2025) 118383] “氧化还原可切割的二硫连接体通过前药型双功能细胞穿透肽增强siRNA递送”的更正[Bioorg]。医学化学，130(2025)118383]。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-12-10 DOI: 10.1016/j.bmc.2025.118513

Keita Wakamori, Yuzuki Hashikawa, Hidehito Urata, Shun-ichi Wada

引用次数: 0

Peptide-based antibiotics: structure-driven strategies to tackle toxicity and resistance of antimicrobial peptides 基于多肽的抗生素：结构驱动的策略来解决抗菌肽的毒性和耐药性

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-11-12 DOI: 10.1016/j.bmc.2025.118486

Maryam Tabarzad , Maryam Torshabi , Azadeh Haeri , Fariba Fathi , Seyedeh Maryam Mortazavi

Antimicrobial peptides (AMPs) are a prominent weapon that can expand human beings' arsenal against antimicrobial resistance. However, microorganisms can equip themselves against the antimicrobial effects of AMPs. Increasing daily dosing of AMPs to dispel resistance may lead to severe side effects or toxicity. In addition, some poor properties of AMPs, such as rapid degradation and low water solubility, make it difficult to achieve the right therapeutic dose at the target site. To provide more potent and less toxic AMPs, structural modification is one of the promising approaches. This review focuses on five representative AMPs: daptomycin, pexiganan (MSI-78), murepavadin (POL7080), iseganan (IB-367), and omiganan (MBI-226), and involves an analysis of their clinical development, mechanisms of resistance, toxicity profiles, and resultant outcomes. By investigating these specific cases, we derive critical insights into the factors influencing the emergence of resistance, the challenges posed by toxicity, and the structural limitations that have impeded the translation of AMPs into clinical applications. Furthermore, we discuss prospective peptide design strategies that may effectively address these challenges. Notably, we underscore the potential of structure-based strategies, including amino acid substitutions and conjugation with diverse molecular entities (such as small functional groups, synthetic polymers, peptides, and antibiotics), as promising pathways to mitigate these barriers and advance the development of clinically viable AMP therapeutics.

抗菌肽（AMPs）是一种重要的武器，可以扩大人类的武器库对抗抗菌素耐药性。然而，微生物可以装备自己对抗抗菌肽的抗菌作用。增加每日剂量的抗菌肽消除耐药性可能导致严重的副作用或毒性。此外，amp的一些较差的特性，如快速降解和低水溶性，使其难以在目标部位达到合适的治疗剂量。为了提供更有效和更低毒性的amp，结构修饰是一种很有前途的方法。本文综述了五种具有代表性的抗菌药物：达托霉素、培昔甘南（MSI-78）、穆里帕瓦丁（POL7080）、伊塞甘南（IB-367）和奥米甘南（MBI-226），并分析了它们的临床发展、耐药机制、毒性特征和结果。通过调查这些具体病例，我们对影响耐药性出现的因素、毒性带来的挑战以及阻碍抗菌肽转化为临床应用的结构限制有了重要的见解。此外，我们讨论了可能有效解决这些挑战的前瞻性肽设计策略。值得注意的是，我们强调了基于结构的策略的潜力，包括氨基酸取代和与不同分子实体（如小官能团、合成聚合物、肽和抗生素）的偶联，作为缓解这些障碍和推进临床可行的AMP治疗方法发展的有希望的途径。

{"title":"Peptide-based antibiotics: structure-driven strategies to tackle toxicity and resistance of antimicrobial peptides","authors":"Maryam Tabarzad , Maryam Torshabi , Azadeh Haeri , Fariba Fathi , Seyedeh Maryam Mortazavi","doi":"10.1016/j.bmc.2025.118486","DOIUrl":"10.1016/j.bmc.2025.118486","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs) are a prominent weapon that can expand human beings' arsenal against antimicrobial resistance. However, microorganisms can equip themselves against the antimicrobial effects of AMPs. Increasing daily dosing of AMPs to dispel resistance may lead to severe side effects or toxicity. In addition, some poor properties of AMPs, such as rapid degradation and low water solubility, make it difficult to achieve the right therapeutic dose at the target site. To provide more potent and less toxic AMPs, structural modification is one of the promising approaches. This review focuses on five representative AMPs: daptomycin, pexiganan (MSI-78), murepavadin (POL7080), iseganan (IB-367), and omiganan (MBI-226), and involves an analysis of their clinical development, mechanisms of resistance, toxicity profiles, and resultant outcomes. By investigating these specific cases, we derive critical insights into the factors influencing the emergence of resistance, the challenges posed by toxicity, and the structural limitations that have impeded the translation of AMPs into clinical applications. Furthermore, we discuss prospective peptide design strategies that may effectively address these challenges. Notably, we underscore the potential of structure-based strategies, including amino acid substitutions and conjugation with diverse molecular entities (such as small functional groups, synthetic polymers, peptides, and antibiotics), as promising pathways to mitigate these barriers and advance the development of clinically viable AMP therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118486"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Biomimetic semi-synthesis, structural optimization and anti-HIV activity of naturally scarce eupholathone-, lathyranone- and integerrimine-type Euphorbia diterpenoids 天然稀缺大戟二萜类化合物的仿生半合成、结构优化及抗hiv活性研究

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-12-05 DOI: 10.1016/j.bmc.2025.118516

Wei Cheng , Peng Wen , Pei-Yin Song , Yang Zhang , Jin-Bu Xu , Steven De Jonghe , Dominique Schols , Feng Gao

Constructing structural diverse compound libraries based on naturally scarce skeletons is a key challenge in natural product medicinal chemistry research. In this study, structural diversification of three classes of naturally scarce Euphorbia diterpenoids (including 5/7/7/4 eupholathones, 6/11/3 lathyranones, and 5/11 integerrimenes) was achieved via a biomimetic skeleton conversion strategy yielding a library of 72 rare Euphorbia diterpenoid analogues, that was investigated as potential inhibitors of HIV replication. The eupholathone type esters exhibited the most potent anti-HIV activity, emerging as a promising class of anti-HIV agents within the Euphorbia diterpenoids family. Analysis of the structure-activity relationship revealed that the hydroxyl group at C6 of the eupholathone scaffold is a critical position for enhancing anti-HIV potency, with aromatic esters on being particularly favorable. Specifically, the eupholathone ester 2t showed the best anti-HIV-1 activity, with an EC₅₀ of 1.51 μM and a selectivity index of more than 66.2, suggesting its potential as a candidate for further antiviral drug development.

基于天然稀缺骨架构建结构多样的化合物文库是天然产物药物化学研究的关键挑战。在这项研究中，通过仿生骨架转换策略，实现了三种天然稀缺的大戟二萜（包括5/7/7/4大戟酮，6/11/3 lathyranones和5/11整合烯）的结构多样化，产生了72种罕见的大戟二萜类类似物，并研究了它们作为HIV复制的潜在抑制剂。大戟拉松型酯类具有较强的抗hiv活性，是大戟二萜类化合物中最有前途的一类抗hiv药物。构效关系分析表明，大胡拉松支架C6羟基是增强抗hiv效力的关键位置，其中芳香酯对增强抗hiv效力尤为有利。其中，大eupholathone酯2t的抗hiv -1活性最高，EC50为1.51 μM，选择性指数大于66.2，表明其具有进一步开发抗病毒药物的潜力。

{"title":"Biomimetic semi-synthesis, structural optimization and anti-HIV activity of naturally scarce eupholathone-, lathyranone- and integerrimine-type Euphorbia diterpenoids","authors":"Wei Cheng , Peng Wen , Pei-Yin Song , Yang Zhang , Jin-Bu Xu , Steven De Jonghe , Dominique Schols , Feng Gao","doi":"10.1016/j.bmc.2025.118516","DOIUrl":"10.1016/j.bmc.2025.118516","url":null,"abstract":"<div><div>Constructing structural diverse compound libraries based on naturally scarce skeletons is a key challenge in natural product medicinal chemistry research. In this study, structural diversification of three classes of naturally scarce <em>Euphorbia</em> diterpenoids (including 5/7/7/4 eupholathones, 6/11/3 lathyranones, and 5/11 integerrimenes) was achieved via a biomimetic skeleton conversion strategy yielding a library of 72 rare <em>Euphorbia</em> diterpenoid analogues, that was investigated as potential inhibitors of HIV replication. The eupholathone type esters exhibited the most potent anti-HIV activity, emerging as a promising class of anti-HIV agents within the <em>Euphorbia</em> diterpenoids family. Analysis of the structure-activity relationship revealed that the hydroxyl group at C6 of the eupholathone scaffold is a critical position for enhancing anti-HIV potency, with aromatic esters on being particularly favorable. Specifically, the eupholathone ester <strong>2t</strong> showed the best anti-HIV-1 activity, with an EC<sub>50</sub> of 1.51 μM and a selectivity index of more than 66.2, suggesting its potential as a candidate for further antiviral drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118516"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Novel indole-based indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors: design, synthesis, and antidepressant evaluation 新型吲哚基吲哚胺2,3-双加氧酶-1 （IDO1）抑制剂：设计、合成和抗抑郁评价

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-12-02 DOI: 10.1016/j.bmc.2025.118503

Juan Zhang , Wen-Jing Gao , Yu-Xi Zheng , Jia-Dong Shao , Nai-Yu Zhang , Wei Guo , Shuai Wang , Qing Zhao , Kongkai Zhu , Ming Gao , Jin-Hai Yu , Ning Meng , Cheng-Shi Jiang

Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor C-0 (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid 9f and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid 10f exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound 10f demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds 9f and 10f had improved in vitro and in vivo pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.

吲哚胺2,3-双加氧酶-1 （IDO1）已成为抗抑郁药物开发的一个有前途的治疗靶点。本研究对已知苯并咪唑衍生的IDO1抑制剂C-0（20.20±2.27 nM）进行了基于支架跳跃的结构优化，得到了一系列新的吲哚基IDO1抑制剂。其中，6-氟吲哚/吲哚-2-羧酰胺杂化物9f和6-氟吲哚/4-溴吡咯-2-羧酰胺杂化物10f的IDO1抑制活性提高最大，IC₅₀值分别为9.18±0.84和6.57±0.61 nM。此外，化合物10f在脂多糖（LPS）刺激的BV-2小胶质细胞中表现出抗炎活性。进一步研究表明，与对照组相比，化合物9f和10f改善了体外和体内药代动力学特性，并挽救了lps诱导的小鼠抑郁样行为。本研究提供了基于吲哚的IDO1抑制剂作为开发新型有效的IDO1靶向抗抑郁药的有希望的先导化合物。

{"title":"Novel indole-based indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors: design, synthesis, and antidepressant evaluation","authors":"Juan Zhang , Wen-Jing Gao , Yu-Xi Zheng , Jia-Dong Shao , Nai-Yu Zhang , Wei Guo , Shuai Wang , Qing Zhao , Kongkai Zhu , Ming Gao , Jin-Hai Yu , Ning Meng , Cheng-Shi Jiang","doi":"10.1016/j.bmc.2025.118503","DOIUrl":"10.1016/j.bmc.2025.118503","url":null,"abstract":"<div><div>Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor <strong>C-0</strong> (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid <strong>9f</strong> and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid <strong>10f</strong> exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound <strong>10f</strong> demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds <strong>9f</strong> and <strong>10f</strong> had improved <em>in vitro</em> and <em>in vivo</em> pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118503"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Polynitrogen-containing compounds as multi-target sEH/FAAH inhibitors: Structure-activity relationship and pharmacological studies 多含氮化合物作为多靶点sEH/FAAH抑制剂：构效关系及药理研究。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-11-20 DOI: 10.1016/j.bmc.2025.118495

Amanda Tsang , Cassandra Yuan , Manuel Berumen , Leah Duong , Karen Gomez , Shelby Seely , Alex Salgado , Adim Rai , Jo Vistosa , Edith Morales Munoz , Marcos E. Ortega , Christophe Morisseau , Bruce D. Hammock , Jake E. Zuckerman , Joseph Yount , Davin G. Piercey , Ram Kandasamy , Stevan Pecic

Both soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are involved in degradation of anti-inflammatory and antinociceptive lipids, thus inhibition of these enzymatic pathways represents a novel strategy in the discovery of non-opioid drugs for treating inflammatory pain. We previously discovered several multi-targeted designed ligands and described a pharmacophore necessary for inhibition of both sEH and FAAH. The potential for optimization on the left side of the pharmacophore led us to exploration of different heterocyclic moieties with the hope to keep strong inhibition potencies, but to increase the metabolic stability and solubility of new analogs. Eighteen analogs containing various substituted and unsubstituted pyrimidinyl-, quinoxalinyl- and tetrazolyl- rings are synthesized and tested for inhibition potency in human FAAH, and human, rat and mouse sEH. The structure-activity relationship study revealed quinoxalinyl- analog 4 m, the most potent dual inhibitor reported to date, with IC₅₀ values of 2.9 nM in human FAAH and 0.7 nM, 39.1 nM and 0.3 nM in human, mouse and rat sEH, respectively. 4 m showed no binding to opioid and most serotonin receptors and was tested in the human, mouse and rat liver microsomes stability assays where it exhibited good and/or moderate clearance rates. Lastly, we evaluated 4 m in vivo in a wheel running assay to determine its effects on voluntary locomotor behavior. Both 4 m and the traditional opioid morphine exhibited significant depression of wheel running after intraperitoneal administration indicating that 4 m may produce undesirable behavioral effects, which will be the basis for future studies.

可溶性环氧化物水解酶（sEH）和脂肪酸酰胺水解酶（FAAH）都参与抗炎和抗疼痛脂质降解，因此抑制这些酶途径代表了发现治疗炎症性疼痛的非阿片类药物的新策略。我们之前发现了几个多靶向设计的配体，并描述了抑制sEH和FAAH所必需的药效团。左侧药效团的优化潜力促使我们探索不同的杂环部分，希望在保持强抑制效力的同时，增加新的类似物的代谢稳定性和溶解度。合成了18种含有不同取代和未取代嘧啶环、喹啉环和四唑基环的类似物，并测试了它们对人FAAH、人、大鼠和小鼠sEH的抑制能力。结构-活性关系研究显示，喹诺沙林基类似物4 m是迄今为止报道的最有效的双抑制剂，其在人FAAH中的IC50值为2.9 nM，在人、小鼠和大鼠sEH中的IC50值分别为0.7 nM、39.1 nM和0.3 nM。4 m显示不与阿片样物质和大多数5 -羟色胺受体结合，并在人、小鼠和大鼠肝微粒体稳定性试验中进行了测试，显示出良好和/或中等的清除率。最后，我们在轮式跑步实验中评估了体内4米，以确定其对自主运动行为的影响。4 m与传统阿片类吗啡腹腔内给药后均表现出明显的轮跑抑制作用，提示4 m可能产生不良的行为效应，这将为今后的研究奠定基础。

{"title":"Polynitrogen-containing compounds as multi-target sEH/FAAH inhibitors: Structure-activity relationship and pharmacological studies","authors":"Amanda Tsang , Cassandra Yuan , Manuel Berumen , Leah Duong , Karen Gomez , Shelby Seely , Alex Salgado , Adim Rai , Jo Vistosa , Edith Morales Munoz , Marcos E. Ortega , Christophe Morisseau , Bruce D. Hammock , Jake E. Zuckerman , Joseph Yount , Davin G. Piercey , Ram Kandasamy , Stevan Pecic","doi":"10.1016/j.bmc.2025.118495","DOIUrl":"10.1016/j.bmc.2025.118495","url":null,"abstract":"<div><div>Both soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are involved in degradation of anti-inflammatory and antinociceptive lipids, thus inhibition of these enzymatic pathways represents a novel strategy in the discovery of non-opioid drugs for treating inflammatory pain. We previously discovered several multi-targeted designed ligands and described a pharmacophore necessary for inhibition of both sEH and FAAH. The potential for optimization on the left side of the pharmacophore led us to exploration of different heterocyclic moieties with the hope to keep strong inhibition potencies, but to increase the metabolic stability and solubility of new analogs. Eighteen analogs containing various substituted and unsubstituted pyrimidinyl-, quinoxalinyl- and tetrazolyl- rings are synthesized and tested for inhibition potency in human FAAH, and human, rat and mouse sEH. The structure-activity relationship study revealed quinoxalinyl- analog <strong>4 m</strong>, the most potent dual inhibitor reported to date, with IC<sub>50</sub> values of 2.9 nM in human FAAH and 0.7 nM, 39.1 nM and 0.3 nM in human, mouse and rat sEH, respectively. <strong>4 m</strong> showed no binding to opioid and most serotonin receptors and was tested in the human, mouse and rat liver microsomes stability assays where it exhibited good and/or moderate clearance rates. Lastly, we evaluated <strong>4 m</strong> in vivo in a wheel running assay to determine its effects on voluntary locomotor behavior. Both <strong>4 m</strong> and the traditional opioid morphine exhibited significant depression of wheel running after intraperitoneal administration indicating that <strong>4 m</strong> may produce undesirable behavioral effects, which will be the basis for future studies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118495"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Broad-spectrum anti-influenza activity of the NMPA-approved drug Pamiparib is uncovered by virtual docking to the evolutionarily conserved domain of IAV-M2 protein 通过虚拟对接IAV-M2蛋白的进化保守结构域，揭示了nmpa批准的药物Pamiparib的广谱抗流感活性

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-12-05 DOI: 10.1016/j.bmc.2025.118518

Min Chen , Huifang Jiao , Dandan Lu , Wenhuan Chen , Zhen Yang , Xue Liang , Pengcheng Wei , Kunpeng Liu

Influenza viruses generate new strains or subtypes through antigenic drift and antigenic shift, leading to the failure of existing antiviral drugs and potentially causing widespread viral infection and influenza epidemics. However, during evolution, certain influenza virus proteins remain unchanged or undergo only minor mutations. Therefore, drugs targeting these evolutionarily conserved viral protein regions may exhibit broad-spectrum antiviral activity across subtypes and against mutations. The purpose of this study is to target the evolutionarily conserved domain of influenza A virus M2 protein and screen for drugs with cross-strain, mutation-resistant, and broad-spectrum antiviral activity. This study used AlphaFold3 to predict the M2 conserved domain structure and employed AutoDock to perform virtual screening of the NMPA database, identifying seven potential candidate drugs. Molecular dynamics simulations indicated that pamiparib exhibits strong affinity for the M2 conserved domain. It demonstrates excellent physiological activity in vitro in inhibiting the replication of H1N1 replication, while showing no effect on other viruses. CETSA experiments confirmed that pamiparib has the potential to bind to the M2 proteins of various influenza virus subtypes. In addition, pamiparib suppresses effectively viral infection in vivo. Ultimately, this study verifies that antiviral drugs designed to target the evolutionarily conserved regions of the influenza virus M2 protein indeed possess broad-spectrum antiviral activity across different strains.

流感病毒通过抗原漂移和抗原转移产生新的毒株或亚型，导致现有抗病毒药物失效，并可能引起广泛的病毒感染和流感流行。然而，在进化过程中，某些流感病毒蛋白保持不变或只发生轻微突变。因此，靶向这些进化上保守的病毒蛋白区域的药物可能在亚型和突变中表现出广谱抗病毒活性。本研究旨在针对甲型流感病毒M2蛋白的进化保守结构域，筛选具有跨株、抗突变和广谱抗病毒活性的药物。本研究使用AlphaFold3预测M2保守结构域结构，并使用AutoDock对NMPA数据库进行虚拟筛选，鉴定出7种潜在的候选药物。分子动力学模拟表明pamiparib对M2保守结构域具有较强的亲和力。在体外对H1N1病毒的复制有良好的抑制作用，而对其他病毒无抑制作用。CETSA实验证实帕米帕尼有可能与各种流感病毒亚型的M2蛋白结合。此外，帕米帕尼还能有效抑制体内病毒感染。最终，本研究验证了针对流感病毒M2蛋白进化保守区域设计的抗病毒药物确实在不同菌株中具有广谱抗病毒活性。

{"title":"Broad-spectrum anti-influenza activity of the NMPA-approved drug Pamiparib is uncovered by virtual docking to the evolutionarily conserved domain of IAV-M2 protein","authors":"Min Chen , Huifang Jiao , Dandan Lu , Wenhuan Chen , Zhen Yang , Xue Liang , Pengcheng Wei , Kunpeng Liu","doi":"10.1016/j.bmc.2025.118518","DOIUrl":"10.1016/j.bmc.2025.118518","url":null,"abstract":"<div><div>Influenza viruses generate new strains or subtypes through antigenic drift and antigenic shift, leading to the failure of existing antiviral drugs and potentially causing widespread viral infection and influenza epidemics. However, during evolution, certain influenza virus proteins remain unchanged or undergo only minor mutations. Therefore, drugs targeting these evolutionarily conserved viral protein regions may exhibit broad-spectrum antiviral activity across subtypes and against mutations. The purpose of this study is to target the evolutionarily conserved domain of influenza A virus M2 protein and screen for drugs with cross-strain, mutation-resistant, and broad-spectrum antiviral activity. This study used AlphaFold3 to predict the M2 conserved domain structure and employed AutoDock to perform virtual screening of the NMPA database, identifying seven potential candidate drugs. Molecular dynamics simulations indicated that pamiparib exhibits strong affinity for the M2 conserved domain. It demonstrates excellent physiological activity in vitro in inhibiting the replication of H1N1 replication, while showing no effect on other viruses. CETSA experiments confirmed that pamiparib has the potential to bind to the M2 proteins of various influenza virus subtypes. In addition, pamiparib suppresses effectively viral infection in vivo. Ultimately, this study verifies that antiviral drugs designed to target the evolutionarily conserved regions of the influenza virus M2 protein indeed possess broad-spectrum antiviral activity across different strains.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118518"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Development of lupeol derivatives based on tubulin-targeting strategy: structural modification and correlation analysis of antitumor activity 基于微管蛋白靶向策略的鹿皮醇衍生物的开发：结构修饰及抗肿瘤活性的相关性分析

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-02-01 Epub Date: 2025-11-24 DOI: 10.1016/j.bmc.2025.118498

Yinxu Zhao , Liman Hou , Shuang Tian , Mengxin Zhu , Jiale Wu , Yukun Ma , Ming Bu , Yu Lin

Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound 5l exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC₅₀) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC₅₀ of human embryonic lung fibroblast MRC-5 cells/IC₅₀ of A549 cells) of 15.39. Mechanistic studies further revealed that compound 5l is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of −13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound 5l demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound 5l holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).

Lupeol是一种天然的五环三萜化合物，作为新型抗肿瘤药物的先导化合物具有很大的开发潜力。为了进一步增强其抗肿瘤活性和靶向能力，本研究设计合成了两个新的芦皮醇衍生物系列，并对3种人类癌细胞系（A549、HepG2和MCF-7）进行了抗增殖活性评价。其中，化合物5l对A549细胞具有较强的体外抗增殖活性，半最大抑制浓度（IC50）为1.84±0.53 μmol/L，选择性指数（SI；人胚胎肺成纤维细胞MRC-5细胞IC50 / A549细胞IC50）为15.39。机制研究进一步表明，化合物5l是一种新型的微管蛋白抑制剂，它能以- 13.40 kcal/mol的结合能特异性结合β-微管蛋白的秋水仙碱结合位点，有效抑制微管蛋白聚合，将细胞周期阻滞在G2/M期，同时引发一系列凋亡相关反应，从而显著诱导肿瘤细胞凋亡。在小鼠肺癌模型中，化合物5l显示出明显的抗肿瘤活性和良好的安全性。基于这些结果，化合物5l有望成为治疗非小细胞肺癌（NSCLC）的新型微管蛋白抑制剂。

{"title":"Development of lupeol derivatives based on tubulin-targeting strategy: structural modification and correlation analysis of antitumor activity","authors":"Yinxu Zhao , Liman Hou , Shuang Tian , Mengxin Zhu , Jiale Wu , Yukun Ma , Ming Bu , Yu Lin","doi":"10.1016/j.bmc.2025.118498","DOIUrl":"10.1016/j.bmc.2025.118498","url":null,"abstract":"<div><div>Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound <strong>5l</strong> exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC<sub>50</sub>) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC<sub>50</sub> of human embryonic lung fibroblast MRC-5 cells/IC<sub>50</sub> of A549 cells) of 15.39. Mechanistic studies further revealed that compound <strong>5l</strong> is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of −13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound <strong>5l</strong> demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound <strong>5l</strong> holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118498"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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