Bioorganic & Medicinal Chemistry最新文献_第6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 : 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。

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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 : 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。

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引用次数: 0

Recent developments in synthesis and antimalarial activities of chalcone hybrids 查尔酮杂合体的合成及抗疟活性研究进展。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-11-29 DOI: 10.1016/j.bmc.2025.118512

Ravindar Lekkala , Revathi Lekkala , Fei Wen Cheong , Nurul Izzaty Hassan , Yee Ling Lau

Malaria remains a significant cause of mortality globally; development and discovery of novel antimalarial drugs are needed to search for effective antimalarial agents due to resistance against existing drugs. Chalcones, also known as α,β-unsaturated ketones, have been studied due to their varied biological activities, including antimalarial activity. Using hybrid compounds is one helpful strategy to enhance the efficacy of antimalarial drugs and reduce treatment resistance. Hence, the current review intended to introduce various heterocycles like triazole, indole, thiophene, benzimidazole, quinoline, piperidine, pyridine, furan, coumarin, and pyrazole containing chalcone hybrids of promising antimalarial activity reported by the researchers from 2019 to 2025. The structure–activity relationship that has been discussed could provide a useful approach for possible drug design and synthesis based on hybridization between the chalcone core and heterocyclic scaffolds.

疟疾仍然是全球死亡的一个重要原因；由于对现有药物的耐药性，需要开发和发现新的抗疟药物来寻找有效的抗疟药物。查尔酮，也被称为α，β-不饱和酮，由于其多种生物活性，包括抗疟疾活性，已被研究。使用杂交化合物是提高抗疟药物疗效和减少治疗耐药性的一种有益策略。因此，本综述旨在介绍2019年至2025年研究人员报告的各种具有抗疟活性的杂环化合物，如三唑、吲哚、噻吩、苯并咪唑、喹啉、哌啶、吡啶、呋喃、香豆素和吡唑等。所讨论的构效关系为基于查尔酮核心与杂环支架之间的杂化设计和合成药物提供了一种有用的方法。

引用次数: 0

Discovery of thiosemicarbazone derivatives as promising SARS-CoV-2 Mpro inhibitors by spectroscopy and microscale thermophoresis 通过光谱和微尺度热电泳发现硫代氨基脲衍生物作为有前途的SARS-CoV-2 Mpro抑制剂。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-11-29 DOI: 10.1016/j.bmc.2025.118501

Xing Xue , Leyao Chen , Miao Zhang , Xiaoyu Chang , Ruiyong Wang

Since the outbreak of COVID-19, one key strategy has been to screen inhibitors of the SARS-CoV-2 main protease (Mpro). Mpro is critical for viral replication and a key target for therapeutic development. In this work, we report the design and synthesis of 29 thiosemicarbazone derivatives. Enzymatic inhibition assays showed that 27 compounds exhibited inhibitory activity against Mpro, among which 4 compounds (1e, 2c, 2f, 3a) demonstrated significant inhibitory potency, with IC₅₀ values of 5.97 ± 0.98 μM, 4.43 ± 1.67 μM, 10.99 ± 2.39 μM, and 28.88 ± 3.57 μM, respectively. Fluorescence spectroscopy, molecular docking, microscale thermophoresis and molecular dynamics simulations were used to analyze the interaction mechanisms between thiosemicarbazone derivatives and Mpro. Fluorescence results indicated that the fluorescence quenching mechanism of the compounds on Mpro was predominantly static quenching. Hydrogen bonding and hydrophobic interactions were observed in the binding process. Microscale thermophoresis results confirmed that compounds 1e, 2c and 2f exhibit significant binding affinity for Mpro, with K_d values of 4.21 ± 0.35 μM, 3.24 ± 0.28 μM, and 24.26 ± 1.82 μM, respectively. This study provides valuable information for understanding the interaction mechanism between thiosemicarbazone derivatives and Mpro and offers insights into novel Mpro inhibitors.

自COVID-19爆发以来，一项关键策略是筛选SARS-CoV-2主要蛋白酶（Mpro）的抑制剂。Mpro对病毒复制至关重要，也是治疗开发的关键靶点。在这项工作中，我们报道了29个硫代氨基脲衍生物的设计和合成。酶促抑制实验表明，27个化合物对Mpro具有抑制活性，其中4个化合物（1e、2c、2f、3a）表现出显著的抑制作用，IC50值分别为5.97±0.98 μM、4.43±1.67 μM、10.99±2.39 μM和28.88±3.57 μM。采用荧光光谱、分子对接、微尺度热电泳和分子动力学模拟等方法分析了硫代氨基脲衍生物与Mpro的相互作用机理。荧光结果表明，化合物在Mpro上的荧光猝灭机制以静态猝灭为主。在结合过程中观察到氢键和疏水相互作用。微尺度热泳实验结果表明，化合物1e、2c和2f对Mpro具有明显的结合亲和力，Kd值分别为4.21±0.35 μM、3.24±0.28 μM和24.26±1.82 μM。本研究为了解硫代氨基脲衍生物与Mpro之间的相互作用机制提供了有价值的信息，并为开发新型Mpro抑制剂提供了见解。

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引用次数: 0

Discovery of novel hybrids of coumarin and quinoline as potential anti-Alzheimer's disease agent 香豆素和喹啉的新型杂交体作为潜在的抗阿尔茨海默病药物的发现。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-11-26 DOI: 10.1016/j.bmc.2025.118499

Shun Li , Xinrui Li , Shuanglong Li, Daoyuan Chen, Chunli Xia

The multifaceted nature of Alzheimer's disease (AD) spurred growing interest in developing multi-target-directed ligands (MTDLs) for its prevention and treatment. Coumarin and quinoline scaffolds, recognized for their broad spectrum of AD-related biological activities including amyloid-β (Aβ) aggregation regulation, cholinesterase (ChE) inhibition, β-secretase 1 (BACE1) inhibition and neuroprotection, were identified as potential building blocks. Here in this study, 24 novel coumarin-quinoline hybrid compounds were rationally designed and synthesized. Inhibition studies targeting Aβ, ChE and BACE1 identified compound B8 as a promising lead compound. B8 exhibited effective binding to Aβ, and significantly attenuated Aβ-induced SH-SY5Y cell death by lowering oxidative stress and decreasing cellular apoptosis. Crucially, B8 demonstrated excellent blood-brain barrier (BBB) permeability, and intragastric administration of B8 to 7-month-old APP/PS1 transgenic mice resulted in improved cognitive function. This improvement was supported by the protection of hippocampal and cortical neurons from necrosis, attenuation of oxidative stress and inflammation in these brain regions, as well as a reduction in Aβ deposition. These findings highlight the potential of coumarin-quinoline hybrids as a novel class of AD therapeutics, with B8 emerging as a promising lead candidate warranting further investigation.

阿尔茨海默病（AD）的多面性促使人们对开发多靶点定向配体（mtdl）来预防和治疗该病越来越感兴趣。香豆素和喹啉支架具有广谱的ad相关生物活性，包括淀粉样蛋白-β (Aβ)聚集调节、胆碱酯酶（ChE）抑制、β-分泌酶1 （BACE1）抑制和神经保护，被认为是潜在的构建基础。本研究合理设计合成了24种新的香豆素-喹啉杂化化合物。针对a β、ChE和BACE1的抑制研究发现，化合物B8是一个很有前景的先导化合物。B8与Aβ有效结合，通过降低氧化应激和减少细胞凋亡，显著减轻Aβ诱导的SH-SY5Y细胞死亡。重要的是，B8表现出良好的血脑屏障（BBB）渗透性，7月龄APP/PS1转基因小鼠灌胃B8可改善认知功能。这种改善是由海马和皮质神经元免受坏死的保护、这些脑区域氧化应激和炎症的衰减以及a β沉积的减少所支持的。这些发现突出了香豆素-喹啉混合物作为一类新型AD治疗药物的潜力，其中B8作为有希望的主要候选药物值得进一步研究。

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引用次数: 0

Development of cationic Pyridinium-Oxazolidinone derivatives as antibacterial agents 阳离子吡啶-恶唑烷酮类抗菌剂的研制。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-11-26 DOI: 10.1016/j.bmc.2025.118502

Maxwell Ampomah-Wireko , Yuequan Wu , Ye Qu , Daran Li , Ruirui Li , Yuanbo Li , Hongtao Kong , Zhi-Hao Li , Cedric Dzidzor Kodjo Amengor , Ya-Na Wang , En Zhang

Drug-resistant bacteria and biofilm-associated infections remain major challenges in anti-infective therapy, contributing to high morbidity and mortality and emphasizing the need to develop novel antimicrobial agents with a low potential to induce resistance. Toward this, quaternization of compounds has become a viable molecular design approach for developing antibacterial agents. In this study, we report the design, synthesis, and antibacterial evaluation of a series of novel ring-C-modified quaternary ammonium oxazolidinone derivatives bearing various lipophilic substituents (alkyl- and aryl-moieties). The structure-activity relationship (SAR) exploration showed that the introduction of longer alkyl chains had a good effect on the antibacterial activity. Compound 4i with longest carbon chain exhibited potent antibacterial activity against E. faecalis with a MIC of 4 μg/mL. Furthermore, this pyridinium oxazolidinone not only exhibited a rapid bactericidal effect but also demonstrated a strong activity against E. faecalis biofilms, with no observable tendency for bacteria to develop resistance to 4i after 20 consecutive passages. Mechanistic studies revealed that 4i disrupted glutathione (GSH)/reactive oxygen species (ROS) homeostasis, thereby inducing lethal oxidative stress, leading to ROS accumulation and bacterial death. Compound 4i also showed low toxicity toward mammalian cells. Overall, our results suggest that incorporating quaternary ammonium salts into oxazolidinones will provide promising strategy for designing novel oxazolidinone derivatives with potent antimicrobial activity and low toxicity against mammalian cells.

耐药细菌和生物膜相关感染仍然是抗感染治疗的主要挑战，导致高发病率和死亡率，并强调需要开发低耐药性的新型抗微生物药物。为此，化合物季铵化已成为开发抗菌剂的一种可行的分子设计方法。在这项研究中，我们报道了一系列新的环c修饰的季铵盐恶唑烷酮衍生物的设计、合成和抗菌评价，这些衍生物含有各种亲脂取代基（烷基和芳基）。构效关系（SAR）研究表明，引入较长的烷基链对抗菌活性有较好的影响。碳链最长的化合物4i对粪肠杆菌具有较强的抗菌活性，MIC为4 μg/mL。此外，该恶唑烷酮吡啶不仅具有快速的杀菌作用，而且对粪肠球菌生物膜具有较强的活性，连续传代20次后细菌对4i无明显的抗性倾向。机制研究表明，4i破坏谷胱甘肽(GSH)/活性氧（ROS）稳态，从而诱导致死性氧化应激，导致ROS积累和细菌死亡。化合物4i对哺乳动物细胞也显示出低毒性。总之，我们的研究结果表明，将季铵盐掺入恶唑烷酮中，将为设计具有强抗菌活性和对哺乳动物细胞低毒性的新型恶唑烷酮衍生物提供有希望的策略。

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引用次数: 0

Benzothiazole sulfones as a tool for peptide modification and cleavage 苯并噻唑砜作为肽修饰和切割的工具。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-11-26 DOI: 10.1016/j.bmc.2025.118500

Phoebe R. Rubio , Gavin A. Clausen , Zachary D. Ruighaver , Abigail F. Dalton, John P. Blobe, Amanda L. Moore, Christopher R. Shugrue

We report the development of a new benzothiazole sulfone (BTS) tool for peptide modification and cleavage. Benzothiazole sulfones are electrophiles that rapidly react with thiols in nucleophilic aromatic substitution (S_NAr) reactions. Alkyne-containing BTS compounds were incorporated onto azidolysine-containing peptides through copper-catalyzed azide-alkyne cycloadditions (CuAACs). BTS-containing peptides were found to react rapidly with two equivalents of thiol nucleophiles at room temperature in 30 min or less. BTS-containing peptides were conjugated to a variety of different compounds, including small molecules, fluorophores, and peptides. Alternatively, a BTS-based cleavable linker could also be synthesized with small molecule cargo, such as biotin, and attached to peptides through CuAAC. This linker enabled the capture and release of a peptide with immobilized streptavidin. The BTS motif is a versatile tool for various applications in peptide science.

我们报道了一种新的用于肽修饰和切割的苯并噻唑砜（BTS）工具的开发。苯并噻唑砜是一种亲电试剂，在亲核芳香取代（SNAr）反应中与硫醇迅速反应。通过铜催化叠氮化物-炔环加成（CuAACs），将含炔的BTS化合物结合到含偶氮赖氨酸的肽上。含bts的多肽在室温下可在30分钟或更短时间内与两种等量的巯基亲核试剂快速反应。含bts的肽被偶联到各种不同的化合物上，包括小分子、荧光团和肽。另外，基于bts的可切割连接体也可以用小分子货物（如生物素）合成，并通过CuAAC连接到肽上。这种连接物使固定链霉亲和素的肽捕获和释放成为可能。BTS基序是肽科学中各种应用的通用工具。

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 : 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。

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引用次数: 0

Unveiling the power of quinazoline derivatives: a new frontier in targeted cancer therapy 揭示喹唑啉衍生物的力量：靶向癌症治疗的新前沿

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-11-23 DOI: 10.1016/j.bmc.2025.118497

Hao-Zhe Long , Meng-Jie Fu , Xin-Qian Ji , Cong-Jun Liu , Bo Wang , Ya Gao , Hui-Min Liu , Yi-Chao Zheng , Hong-Min Liu , Xing-Jie Dai

Quinazoline-based scaffolds represent a class of nitrogen-containing heterocycles distinguished by their structural versatility and broad-spectrum anticancer activities, positioning them as key elements in targeted cancer therapy. This review highlights the role of quinazoline derivatives as potent small-molecule inhibitors targeting diverse oncogenic drivers. They effectively modulate critical receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and cellular-mesenchymal epithelial transition factor (c-Met); non-receptor serine/threonine kinases including cyclin-dependent kinases (CDKs), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Aurora kinases, and hematopoietic progenitor kinase 1 (HPK1); as well as epigenetic, cytoskeletal, and DNA-interacting proteins. Recent advances in structure-activity relationship (SAR) studies, binding analyses, and preclinical evaluations have facilitated scaffold optimization to counter resistance mutations and improve pharmacokinetic properties. Collectively, clinical and experimental evidence underscores quinazoline derivatives as a robust platform for developing next-generation targeted anticancer agents.

基于喹唑啉的支架是一类含氮杂环化合物，其结构多功能性和广谱抗癌活性使其成为靶向癌症治疗的关键元素。这篇综述强调了喹唑啉衍生物作为针对多种致癌驱动因素的有效小分子抑制剂的作用。它们能有效调节关键受体酪氨酸激酶（rtk），如表皮生长因子受体（EGFR）、人表皮生长因子受体2 （HER2）、血管内皮生长因子受体（VEGFR）、成纤维细胞生长因子受体（FGFR）、血小板衍生生长因子受体（PDGFR）和细胞间充质上皮转化因子（c-Met）；非受体丝氨酸/苏氨酸激酶，包括细胞周期蛋白依赖性激酶（CDKs）、磷酸肌肽3-激酶(PI3K)/蛋白激酶B (AKT)/哺乳动物雷帕霉素靶蛋白（mTOR）、极光激酶和造血祖激酶1 (HPK1)；以及表观遗传、细胞骨架和dna相互作用蛋白质。结构-活性关系（SAR）研究、结合分析和临床前评估的最新进展促进了支架优化以对抗耐药突变和改善药代动力学特性。总的来说，临床和实验证据强调喹唑啉衍生物是开发下一代靶向抗癌药物的强大平台。

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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 : 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。

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引用次数: 0