European Journal of Medicinal Chemistry Reports最新文献_第4页

Molecules with alkyne fragment in medicinal chemistry: The path from neurotoxins to drugs 药物化学中的炔片段分子：从神经毒素到药物的途径

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-08-18 DOI: 10.1016/j.ejmcr.2025.100294

Nataliya Zelisko , Roman Lesyk

In this comprehensive review, we explore a diverse array of highly promising compounds, categorized based on their pharmacological properties, origins, and synthetic methodologies, to highlight the critical role of alkyne functionalities in advancing medicinal chemistry. Our analysis underscores the unique contributions of acetylene-containing compounds, emphasizing their structural significance and therapeutic potential.

The remarkable versatility of acetylene-bearing molecules is evident in their wide-ranging biological activities, which position them as exceptional candidates for drug development. Extensive studies compiled in this review demonstrate that incorporating an acetylene group into molecular frameworks significantly enhances bioactivity. Numerous naturally occurring alkynes exhibit potent antibacterial, antifungal, and anticancer effects. Notably, compounds featuring a propargylamine group are established inhibitors of monoamine oxidase (MAO) and cholinesterases (ChEs). Additionally, a range of alkyne derivatives shows promise as H3-receptor antagonists, offering potential treatments for conditions such as epilepsy, depression, schizophrenia, Parkinson's disease, Alzheimer's disease, sleep disorders, attention deficit hyperactivity disorder, and various inflammatory and gastrointestinal disorders. Acetylene-containing compounds also play a role in anti-HIV therapies, with certain synthetic steroids falling within this class. Furthermore, alkynes are integral to multi-target-directed ligand (MTDL) strategies, broadening their therapeutic applications.

A particular focus of this review is the compelling anticancer potential of MAO inhibitors, which have garnered significant attention from pharmaceutical companies for their efficacy against prostate cancer, Hodgkin lymphoma, glioma brain tumors, non-small cell lung cancer, A-2058 melanoma cell lines, and acute myeloid leukemia. This has spurred interest in drug repurposing, establishing these compounds as a cornerstone of innovative therapeutic development.

在这篇全面的综述中，我们根据其药理性质、来源和合成方法对各种极具前景的化合物进行了分类，以突出炔官能团在推进药物化学中的关键作用。我们的分析强调了含乙炔化合物的独特贡献，强调了它们的结构意义和治疗潜力。含乙炔分子的显著多功能性在其广泛的生物活性中是显而易见的，这使它们成为药物开发的特殊候选者。大量的研究表明，在分子框架中加入乙炔基团可以显著提高生物活性。许多天然存在的炔具有强大的抗菌、抗真菌和抗癌作用。值得注意的是，含有丙胺基团的化合物是单胺氧化酶（MAO）和胆碱酯酶（ChEs）的抑制剂。此外，一系列炔衍生物显示出作为h3受体拮抗剂的前景，为癫痫、抑郁症、精神分裂症、帕金森病、阿尔茨海默病、睡眠障碍、注意缺陷多动障碍以及各种炎症和胃肠道疾病等疾病提供潜在的治疗方法。含乙炔的化合物也在抗hiv治疗中发挥作用，某些合成类固醇就属于这一类。此外，炔烃是多靶点定向配体（MTDL）策略的组成部分，扩大了它们的治疗应用。本综述的一个特别重点是MAO抑制剂的抗癌潜力，由于其对前列腺癌、霍奇金淋巴瘤、胶质瘤脑肿瘤、非小细胞肺癌、A-2058黑色素瘤细胞系和急性髓性白血病的疗效，引起了制药公司的极大关注。这激发了人们对药物再利用的兴趣，使这些化合物成为创新治疗发展的基石。

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引用次数: 0

Cheminformatics in advancing dengue antiviral research: From conventional molecular modeling (MM) to current artificial intelligence (AI) approaches 化学信息学在推进登革热抗病毒研究中的作用：从传统的分子建模（MM）到当前的人工智能（AI）方法

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-08-16 DOI: 10.1016/j.ejmcr.2025.100295

Rinki Prasad Bhagat , Sk Abdul Amin , Lucia Sessa , Simona Concilio , Stefano Piotto , Shovanlal Gayen

Cheminformatics has rapidly evolved and garnered widespread attention due to its potential to accelerate the process and reduce the cost of drug design and development. These technologies play a crucial role in drug design against dengue virus (DENV), a neglected tropical disease that remains a significant global health burden, with millions of cases reported annually. Recent advancements in cheminformatics and artificial intelligence (AI)-driven approaches offer promising strategies for designing inhibitors targeting key viral proteins. This study explores the applications of various cheminformatics methods, including conventional molecular modeling (pharmacophore mapping, molecular docking, molecular dynamics (MD) simulations, virtual screening), and artificial intelligence (AI)/machine learning (ML)-based strategies reported to identify compounds with high affinity and specificity for critical DENV protein targets. Additionally, it highlights the synergy between experimental validation, and in silico predictions to prioritize candidate molecules for further development.

化学信息学迅速发展，并引起了广泛的关注，因为它有可能加快过程，降低药物设计和开发的成本。这些技术在针对登革热病毒（DENV）的药物设计中发挥着至关重要的作用。登革热病毒是一种被忽视的热带病，仍然是全球重大的卫生负担，每年报告有数百万病例。化学信息学和人工智能（AI）驱动方法的最新进展为设计针对关键病毒蛋白的抑制剂提供了有前途的策略。本研究探索了各种化学信息学方法的应用，包括传统的分子建模（药效团定位、分子对接、分子动力学（MD）模拟、虚拟筛选），以及基于人工智能(AI)/机器学习（ML）的策略，以识别对关键DENV蛋白靶点具有高亲和力和特异性的化合物。此外，它强调了实验验证和计算机预测之间的协同作用，以优先考虑候选分子以进一步开发。

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引用次数: 0

Screening of G-quadruplex DNA ligands by fluorescence detection of peptide displacement 利用肽位移荧光检测筛选g -四重体DNA配体

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-08-07 DOI: 10.1016/j.ejmcr.2025.100293

Valentina Arciuolo , Simona Marzano , Rossella Buono, Nicola Grasso, Anna Di Porzio, Antonio Randazzo, Bruno Pagano, Jussara Amato

G-quadruplexes (G4s) are noncanonical DNA/RNA structures involved in key cellular processes, and their interactions with proteins are emerging as therapeutic targets. However, strategies to identify ligands that bind G4s and potentially modulate these interactions remain limited. Here, we describe a fluorescence-based assay for rapid, quantitative evaluation of small molecules that bind G4s and potentially interfere with protein recognition. The method employs a fluorophore-labeled peptide derived from a conserved G4-binding protein motif, and a G4-forming sequence labeled with a fluorescence acceptor. Ligand-induced peptide displacement is detected via fluorescence increase. A panel of known G4 ligands was tested, and results correlated with binding affinities. A duplex DNA competition assay further assessed ligand selectivity. This method provides a scalable tool for screening G4 ligands with ability to compete with G4-recognition motifs, supporting drug discovery efforts.

g -四plex （G4s）是参与关键细胞过程的非规范DNA/RNA结构，它们与蛋白质的相互作用正成为治疗靶点。然而，鉴定结合G4s并可能调节这些相互作用的配体的策略仍然有限。在这里，我们描述了一种基于荧光的检测方法，用于快速定量评估结合G4s并可能干扰蛋白质识别的小分子。该方法采用从保守的g4结合蛋白基序衍生的荧光团标记肽，以及用荧光受体标记的g4形成序列。通过荧光增加检测配体诱导的肽位移。对一组已知的G4配体进行了测试，结果与结合亲和力相关。双链DNA竞争分析进一步评估了配体的选择性。该方法提供了一种可扩展的工具，用于筛选具有与G4识别基序竞争能力的G4配体，支持药物发现工作。

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引用次数: 0

Dual-target candidate compounds from a transformer chemical language model contain characteristic structural features 从变压器化学语言模型的双目标候选化合物包含特征的结构特征

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-07-30 DOI: 10.1016/j.ejmcr.2025.100291

Sanjana Srinivasan , Alec Lamens , Jürgen Bajorath

Chemical language models (CLMs) are increasingly used for generative design of candidate compounds for medicinal chemistry. However, their predictions are difficult to rationalize. Currently, detailed computational explanations of CLM-based compound generation are unavailable. Therefore, we have attempted to better understand from a medicinal chemistry perspective how CLMs learn and arrive at compound predictions. Therefore, we have subjected dual-target candidate compounds for polypharmacology generated with transformer CLMs to a series of analysis steps exploring structural features that are learned and compared them to known compounds with dual-target activity. Using machine learning combined with distinct chemical structure-oriented approaches from explainable artificial intelligence, we show that CLMs learn substructures characteristic of known dual-target compounds as a basis for generating new candidates with various chemical modifications.

化学语言模型（CLMs）越来越多地用于药物化学候选化合物的生成设计。然而，他们的预测很难合理化。目前，还没有基于clm的化合物生成的详细计算解释。因此，我们试图从药物化学的角度更好地理解clm是如何学习和达到化合物预测的。因此，我们对由变压器CLMs生成的多药理学的双靶点候选化合物进行了一系列分析步骤，探索所了解的结构特征，并将它们与具有双靶点活性的已知化合物进行比较。利用机器学习与可解释人工智能的不同化学结构导向方法相结合，我们表明clm学习已知双靶化合物的亚结构特征，作为生成具有各种化学修饰的新候选化合物的基础。

引用次数: 0

Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor 新型三唑基香豆素类化合物作为乙酰胆碱酯酶抑制剂：3-乙酰基香豆素系（2-溴苯基）-1,2,3三唑作为潜在混合型抑制剂的证据和机制

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-07-30 DOI: 10.1016/j.ejmcr.2025.100289

Naseer Ahmad Dar , Owais Hassan Wani , Yuanyuan Wang , Faez Iqbal Khan , Bilal A. Ganie , Syed Wajaht A. Shah , Tanveer Ali Dar , Tabasum Ismail

Acetylcholinesterase (AChE) inhibition remains an important therapeutic strategy for Alzheimer's diseases, prompting immense research for novel and efficient small-molecule inhibitors. In this context, the present study describes the synthesis, characterization and evaluation of novel ether-linked 3-acetyl triazole-substituted coumarin derivatives as potential AChE inhibitors. The synthetic route involved 3-acetyl-7-hydroxycoumarin preparation through the reaction of 2,4-dihydoxybenzaldehyde with ethyl acetoacetate. Following alkylation at hydroxyl group, the acetylated 7-hydroxycoumarin underwent 1,3-dipolar cycloaddition i.e., Huisgen cycloaddition with various aromatic azides under sharpless click chemistry conditions, leading to the formation of a library of 16 novel coumarin tethered 1,2,3-triazole derivatives. Following synthesis and characterization using ¹H NMR, ¹³C NMR and IR spectroscopy, the AChE inhibitory potential of the coumarin derivatives was assessed, yielding IC₅₀ value in the range of 2.18 μM–67.89 μM. Among them, compound 9 exhibited the most potent inhibition (IC₅₀ = 2.18 μM), although lower than that of the standard inhibitor, eserine. Kinetic analysis indicated that compound 9 acted as a mixed-type inhibitor, with a K_i of 8.13 ± 0.18 μM. In silico simulation analysis elucidated the critical interactions between compound 9 and key AChE residues, including hydrogen bonding with Tyr121 and His444 and π-π stacking with Tyr334 and Trp283, supporting its strong binding affinity for the enzyme. Furthermore, the binding free energy calculations also confirmed the favourable thermodynamic interactions between the compound 9 and AChE. Collectively, the present findings highlight the therapeutic potential of compound 9 and establish this novel coumarin-triazole scaffold as a promising lead candidate for further optimization in development of AChE-targeted Alzheimer's therapeutics.

乙酰胆碱酯酶（AChE）抑制仍然是阿尔茨海默病的重要治疗策略，促进了对新型高效小分子抑制剂的大量研究。在此背景下，本研究描述了新型醚连接的3-乙酰三唑取代香豆素衍生物作为潜在的AChE抑制剂的合成，表征和评价。合成路线为2,4-二羟基苯甲醛与乙酰乙酸乙酯反应制备3-乙酰-7-羟基香豆素。在羟基上烷基化后，乙酰化的7-羟基香豆素在无尖键化学条件下与各种芳香叠氮化物进行1,3-偶极环加成，即Huisgen环加成，形成了16个新的香豆素系1,2,3-三唑衍生物库。采用1H NMR、13C NMR和IR对香豆素衍生物进行合成和表征，得到IC50值在2.18 μM - 67.89 μM范围内。其中化合物9的IC50值为2.18 μM，但低于标准抑制剂eserine的IC50值。动力学分析表明，化合物9为混合型抑制剂，Ki为8.13±0.18 μM。硅模拟分析阐明了化合物9与AChE关键残基之间的关键相互作用，包括与Tyr121和His444的氢键和与Tyr334和Trp283的π-π堆叠，支持其对酶的强结合亲和力。此外，结合自由能的计算也证实了化合物9与AChE之间良好的热力学相互作用。总之，目前的研究结果突出了化合物9的治疗潜力，并确立了这种新型香豆素-三唑支架作为进一步优化开发针对疼痛的阿尔茨海默病治疗药物的有希望的先导候选物。

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引用次数: 0

In silico and In vitro profiling of lariciresinol against PLA2: A molecular approach to regulate inflammation 松柏树脂醇抗PLA2的硅和体外分析：一种调节炎症的分子方法

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-07-26 DOI: 10.1016/j.ejmcr.2025.100290

Fathimath Henna , G. Arun Kumar , Amritha Thaikkad , T.K. Varun , E. Jayadevi Variyar , Rajesh Raju , J. Abhithaj

Chronic inflammation underlies various diseases, including cardiovascular disorders, cancer, and autoimmune conditions. Phospholipase A2 (PLA2) plays a central role in the inflammatory response by hydrolyzing membrane phospholipids to release arachidonic acid, a precursor for pro-inflammatory eicosanoids via the COX and LOX pathways. Due to its upstream regulatory function, PLA2 presents a strategic target for inflammation control. However, developing safe and effective PLA2 inhibitors remains challenging due to limitations in efficacy and side effects.

Natural compounds, particularly phytochemicals with anti-inflammatory potential, are gaining attention as alternative therapeutics. This study investigated Lariciresinol, a phenolic lignan from Zingiber officinale (ginger), for its inhibitory activity against PLA2. Selected through in silico screening, Lariciresinol was evaluated using molecular docking, molecular dynamics (MD) simulations, and in vitro enzyme inhibition assays. The compound showed competitive inhibition with an IC50 of 57.6μM. The binding energy of Lariciresinol improved from −24.71kcal/mol to −34.38kcal/mol after MD simulations. The results from the binding energy analysis and MD simulations revealed stable interactions with key catalytic residues, supporting its proposed mechanism of action.

Further in silico analysis of Root Mean Square Deviation, Root Mean Square Fluctuation, Radius of Gyration, H-bonds, Solvent Accessible Surface Area, and Free Energy Landscape validated the results. These results highlight Lariciresinol a promising scaffold for developing novel PLA2-targeted anti-inflammatory agents, warranting further in vitro and in vivo validation for clinical application.

慢性炎症是多种疾病的基础，包括心血管疾病、癌症和自身免疫性疾病。磷脂酶A2 （PLA2）在炎症反应中发挥核心作用，通过水解膜磷脂释放花生四烯酸，花生四烯酸是促炎性类二十烷酸的前体，通过COX和LOX途径。由于其上游调控功能，PLA2是炎症控制的战略靶点。然而，由于疗效和副作用的限制，开发安全有效的PLA2抑制剂仍然具有挑战性。天然化合物，特别是具有抗炎潜力的植物化学物质，作为替代疗法正受到越来越多的关注。本文研究了姜中酚类木脂素Lariciresinol对PLA2的抑制作用。通过硅筛选筛选，利用分子对接、分子动力学（MD）模拟和体外酶抑制试验对落叶松树脂醇进行了评价。该化合物具有竞争性抑制作用，IC50为57.6μM。MD模拟后，落叶松树脂的结合能从−24.71kcal/mol提高到−34.38kcal/mol。结合能分析和MD模拟的结果表明，该化合物与关键催化残基的相互作用稳定，支持了其作用机制。进一步的均方根偏差、均方根波动、旋转半径、氢键、溶剂可及表面积和自由能景观的计算机分析验证了结果。这些结果表明，落叶松醇是开发新型pla2靶向抗炎药的有希望的支架，值得进一步的体外和体内临床应用验证。

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引用次数: 0

Glaucumolides C-P, cembrane-type diterpenoids from the marine soft coral Sarcophyton glaucum with potential attenuating activities against IgAN nephropathy 来自海洋软珊瑚青光石的膜型二萜类化合物C-P对IgAN肾病具有潜在的减弱作用

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-07-25 DOI: 10.1016/j.ejmcr.2025.100287

Kang Zhou , Jian Huang , Hongli Jia , Pianpian Wang , Bin Wang , Wei Cheng , Wenhan Lin

Cembranoids represent a class of diterpenes, featuring a cyclotetradecadiene backbone substituted by an isopropyl residue and three methyl groups with diverse subtypes and a panel of bioactivities. In this study, molecular networking-based metabolomic analysis revealed the soft coral Sarcophyton glaucum containing a chemical profile of cembrane-type diterpenes. Targeted isolation of the diterpene-enriched fractions resulted in the isolation of 14 undescribed cembranoids, namely glaucumolides C-P (1–14). Their structures were determined by extensive spectroscopic data in association with the X-ray diffraction and electronic circular dichroism (ECD) data for configurational assignments. All analogs featured an unsaturated γ-lactone in the backbone. Glaucumolide M and metabolite-A exhibited significant inhibition against the proliferation of lipopolysaccharide (LPS)-induced DAKIKI cells, and upregulated the expression of mRNA of C1GalT1 and its chaperone Cosmc in DAKIKI cells dose-dependently. Those findings suggest glaucumolides to be potential to prevent imunoglobulin A (IgA) nephropathy.

类cembranoid是一类二萜化合物，具有一个环十四二烯主链被一个异丙基残基取代，三个甲基具有不同的亚型和一组生物活性。在这项研究中，基于分子网络的代谢组学分析揭示了软珊瑚Sarcophyton glaucum含有膜型二萜的化学特征。对富含二萜的组分进行定向分离，分离出14种未描述的膜类化合物，即青绿毛酸酯C-P（1-14）。它们的结构是通过大量的光谱数据，结合x射线衍射和电子圆二色性（ECD）数据来确定的。所有类似物的主链中都含有不饱和γ-内酯。青苔内酯M和代谢产物a对脂多糖（LPS）诱导的DAKIKI细胞增殖有显著抑制作用，并呈剂量依赖性上调DAKIKI细胞中C1GalT1及其伴侣蛋白Cosmc mRNA的表达。这些发现表明青铜绿内酯具有预防免疫球蛋白A （IgA）肾病的潜力。

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引用次数: 0

Triazenes as inhibitors of HIV-1 and HCoV-OC43: A structure-activity relationship study 三氮杂烯作为HIV-1和HCoV-OC43抑制剂的构效关系研究

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-07-21 DOI: 10.1016/j.ejmcr.2025.100288

Natacha Mérindol , Seyedeh Mahsa Hashemian , Seynabou Sokhna , Marie-Pierre Girard , Marc Presset , Insa Seck , Lalla Aïcha Ba , Seydou Ka , Samba Fama Ndoye , Issa Samb , Erwan Le Gall , Lionel Berthoux , Matar Seck , Isabel Desgagné-Penix

Triazenes, or amino-substituted diazenes, are organic compounds containing three contiguous nitrogen atoms, that have potent biological activities. We previously demonstrated that triazenes, particularly those substituted with a phenyl or 3-pyridyl ring at the 1-position and a 2-pyridyl ring at the 3-position, exhibit anti-DENV properties. Here, we evaluated the antiviral activity against a betacoronavirus (HCoV-OC43) and a lentivirus (HIV-1). 1-(4-trifluoromethylphenyl)-2-imidazole-1-yldiazene (21) exhibited broad-spectrum activity (EC₅₀ = 6.6–6.8 μM) but was cytotoxic to THP-1 cells. Pyridyl triazenes (14, 15) were the most potent against HCoV-OC43, while 1-(4-methoxyphenyl)-2-morpholin-4-yldiazene (6) and 1-(4-methoxyphenyl)3-(-6-methylpyridin-2-yl)triazene (10) inhibited HIV-1 the most. Structure–activity relationship analysis, supported by molecular docking, indicated that para-methoxy groups favored interactions with viral enzyme binding pockets, enhancing antiviral potency, while meta and para-trifluoromethyl groups were associated with reduced activity and increased cytotoxicity. These findings support the further development of triazenes as antiviral scaffolds.

三氮杂烯或氨基取代二氮杂烯是含有三个相邻氮原子的有机化合物，具有强大的生物活性。我们之前已经证明，三氮杂烯，特别是那些在1位被苯基或3-吡啶环取代，在3位被2-吡啶环取代的三氮杂烯，具有抗denv特性。在这里，我们评估了对乙型冠状病毒（HCoV-OC43）和慢病毒（HIV-1）的抗病毒活性。1-（4-三氟甲基苯基）-2-咪唑-1-基二氮烯（21）具有广谱活性（EC50 = 6.6 ~ 6.8 μM），但对THP-1细胞具有细胞毒性。吡啶基三氮杂烯（14,15）对HCoV-OC43的抑制作用最强，而1-（4-甲氧基苯基）-2-morpholin-4-yldiazene(6)和1-（4-甲氧基苯基）3-（-6-甲基吡啶-2-基）三氮杂烯（10）对HIV-1的抑制作用最强。基于分子对接的构效关系分析表明，对甲氧基倾向于与病毒酶结合口袋相互作用，增强抗病毒效力，而间和对三氟甲基则与活性降低和细胞毒性增加相关。这些发现支持了三氮杂烯作为抗病毒支架的进一步发展。

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引用次数: 0

New cytotoxic dolabellane and dolastane diterpenes from Brown seaweed Dictyota dichotoma 褐藻中新的细胞毒性一元藻烷和一元藻烷二萜

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-07-17 DOI: 10.1016/j.ejmcr.2025.100286

Kolukula Ashwini , Bandi Siva , Penta Poornima , Solipeta Divya Reddy , Hashnu Dutta , Vedula Girija Sastry , Katragadda Suresh Babu

Five new dolabellane (1–5), three dolastane (6–8) type diterpenes together with five previously identified congeners (9–13), were isolated from the organic extracts of the brown seaweed Dictyota dichotoma, collected in the Mandapam coast, Tamil Nadu. The structures and relative stereochemistry of the new isolates 1–8 were determined on the basis of extensive spectroscopic (NMR and Mass spec) data, whereas the structures of 10 and 12 were verified by X-ray diffraction analysis. A plausible biogenetic relationship between undescribed compounds 1–8 were also proposed. The in vitro anti-cancer activity of the isolates was examined against a panel of cancer cell lines, including DU145 (prostate), B16F10 (melanoma), HeLa (cervical), and MDA-MB231 (breast) using MTT assay. The screening results showed that majority of the isolated compounds exhibited moderate to potent activities against tested cell lines. Among the tested, compounds 4 and 7 manifested potent activities with an IC₅₀ value of 3.53 ± 0.05 and 2.18 ± 0.06 μM respectively, against B16F10 and DU145 cells. Further, detailed fluorescence assays, scratch assay and flow cytometry analysis revealed that the compounds 4 and 7 diminished proliferation and arrested cell cycle in the G0 phase and G0/G1 phase, which induced cell death by apoptosis. Overall, this study provided that compounds 4 and 7 could serve as lead molecules for the development of potent anti-cancer agents.

从泰尔纳德邦Mandapam海岸采集的褐藻Dictyota dichotoma有机提取物中分离出5个新的dolabellane（1-5）、3个dolabellane（6-8）型二萜和5个先前鉴定的同源物（9-13）。新分离物1 ~ 8的结构和相对立体化学是通过广泛的波谱（NMR和质谱）数据确定的，10和12的结构是通过x射线衍射分析验证的。还提出了未描述的化合物1-8之间似是而非的生物遗传学关系。采用MTT法检测分离物对一系列癌细胞系的体外抗癌活性，包括DU145（前列腺）、B16F10（黑色素瘤）、HeLa（宫颈癌）和MDA-MB231（乳腺癌）。筛选结果表明，大多数分离的化合物对所测试的细胞系具有中等到强效的活性。其中化合物4和7对B16F10和DU145细胞的IC50值分别为3.53±0.05和2.18±0.06 μM。荧光、划痕实验和流式细胞术分析显示，化合物4和7抑制细胞增殖，阻滞G0期和G0/G1期细胞周期，诱导细胞凋亡死亡。综上所述，化合物4和7可以作为先导分子开发有效的抗癌药物。

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引用次数: 0

Naphthalimide-polyamine conjugates: a promising avenue for targeted anticancer therapy 萘酰亚胺-多胺缀合物：一种有前途的靶向抗癌治疗途径

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-07-10 DOI: 10.1016/j.ejmcr.2025.100285

Zhiyong Tian , Luyao Tian , Chaojie Wang

Although chemotherapy is fundamental in cancer therapy, its effectiveness is restricted by systemic toxicity and drug resistance. By combining DNA intercalation, topoisomerase inhibition, and tumor microenvironment modulation, naphthalimide-polyamine conjugates have emerged as promising agents targeting multiple pathways. This review explores how structural innovations in conjugates can overcome therapeutic resistance and minimize off-target effects. In the past, early derivatives such as amonafide encountered clinical challenges because of dose-limiting myelosuppression (e.g., >400 mg/m²). Nonetheless, recent progress in polyamine-mediated targeting and nanocarrier delivery has rejuvenated this class. We present a new Type I-VII classification approach that relates structural modifications—like heterocyclic fusion, polyamine chain adjustments, and substituent effects—to mechanistic outcomes. For example, compounds such as BND-12 inhibit metastasis in hepatocellular carcinoma by 61.8 % through ROS-induced mitochondrial dysfunction, whereas LU-79553 shows sub-micromolar effectiveness (IC₅₀ ≤ 0.32 μM) in colorectal cancer with minimal hematotoxicity. Key advancements include: (1) Triple-action synergy, which simultaneously induces DNA damage through p53/PARP-1, disrupts autophagy regulation, and inhibits VEGF/MMP, thereby interfering with adaptive resistance mechanisms. (2) Targeted delivery: The use of polyamine transporters (PAT) and nanocarriers boosts tumor selectivity, as shown by compound 17, which reduces cisplatin resistance by 2–9 times by depleting lysosomal polyamines. (3) Structure-activity relationship (SAR) design: Adding a chlorine atom at the C₄ position, such as in 4-ClNAHSPD, enhances DNA binding affinity (Kb = 1.7 × 10⁴ M⁻¹) and increases γ-H₂AX foci formation by 1.8 times, while rigid cycloalkanediamine linkers improve cell cycle arrest. Preclinical success has been achieved, yet problems with metabolic stability and neurotoxicity persist. Future research focuses on AI-driven polyamine enhancement, nanoplatforms that can cross the blood-brain barrier (such as Angiopep-2-functionalized Ti@FeAu), and non-apoptotic cell death mechanisms like pyroptosis. Through the integration of structural innovation and multi-mechanistic synergy, this research sets up a design framework for precision oncology, illustrated by AI-optimized polyamine chains and nanoplatforms capable of crossing the blood-brain barrier. These methods provide a practical strategy for future cancer therapies aimed at overcoming adaptive resistance.

虽然化疗是癌症治疗的基础，但其有效性受到全身毒性和耐药性的限制。通过结合DNA嵌入、拓扑异构酶抑制和肿瘤微环境调节，萘酰亚胺-多胺缀合物已成为靶向多种途径的有前途的药物。这篇综述探讨了如何结构创新的缀合物可以克服治疗耐药性和最小化脱靶效应。在过去，早期的衍生品如氨硝胺由于剂量限制的骨髓抑制（例如，400 mg/m2）而遇到了临床挑战。尽管如此，最近在多胺介导的靶向和纳米载体递送方面的进展使这类药物重新焕发了活力。我们提出了一种新的I-VII型分类方法，将结构修饰（如杂环融合、多胺链调整和取代基效应）与机制结果联系起来。例如，BND-12等化合物通过ros诱导的线粒体功能障碍对肝癌转移的抑制作用为61.8%，而LU-79553对结直肠癌的亚微摩尔效应（IC50≤0.32 μM）具有最小的血液毒性。主要进展包括：(1)三作用协同，通过p53/PARP-1同时诱导DNA损伤，破坏自噬调节，抑制VEGF/MMP，从而干扰适应性耐药机制。(2)靶向给药：多胺转运体（PAT）和纳米载体的使用提高了肿瘤的选择性，如化合物17所示，通过消耗溶酶体多胺，使顺铂耐药性降低2 - 9倍。(3)构效关系（SAR）设计：在C4位置添加一个氯原子，例如在4-ClNAHSPD中，增强了DNA结合亲和力（Kb = 1.7 × 104 M−1），并使γ-H2AX灶形成增加了1.8倍，而刚性环烷二胺连接体改善了细胞周期阻滞。临床前已取得成功，但代谢稳定性和神经毒性问题仍然存在。未来的研究重点是人工智能驱动的多胺增强，可以穿过血脑屏障的纳米平台（如angiopep -2功能化Ti@FeAu），以及非凋亡细胞死亡机制，如焦亡。通过结构创新和多机制协同的整合，本研究建立了以人工智能优化的多胺链和能够跨越血脑屏障的纳米平台为代表的精准肿瘤学设计框架。这些方法为未来的癌症治疗提供了一种实用的策略，旨在克服适应性耐药性。

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