Bioorganic Chemistry最新文献_第4页

A nature-inspired peptide from the Boana cordobae frog as a potent and reversible AChE inhibitor with anti-amyloid and neuroprotective activities 一种受自然启发的肽，来自于Boana cordobae蛙，作为一种有效的可逆乙酰胆碱酯酶抑制剂，具有抗淀粉样蛋白和神经保护活性

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-27 DOI: 10.1016/j.bioorg.2026.109566

Roque Spinelli , Ivan Sanchis , Milagros de Orellana , Maria Veronica Humpola , Álvaro Rietmann , Álvaro Sebastían Siano

Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder for which no effective treatment currently exists. The development of multitarget-directed ligands (MTDLs) capable of simultaneously modulating several pathological pathways represents a rational strategy to address its complex etiology. In this study, we report the isolation, chemical synthesis, and functional characterization of BcI-4, a short cationic peptide identified from the skin secretion of the Argentinean frog Boana cordobae. The peptide exhibited potent and reversible inhibitory activity against acetylcholinesterase (AChE), with IC₅₀ values of 1.10 and 0.9 μM for recombinant human and Electrophorus electricus AChE, respectively, acting through a non-competitive mechanism involving the peripheral anionic site (PAS). BcI-4 also inhibited AChE-induced β-amyloid (Aβ) aggregation, showed modest monoamine oxidase B (MAO-B) inhibition, and displayed both antioxidant and metal-chelating activities, including inhibition of lipid peroxidation. The peptide retained the multifuctional pharmacological profile previously observed for the crude extract of B. cordobae, with significantly enhanced potency and selectivity toward AChE. Moreover, BcI-4 was non-toxic in vitro (hemolysis and HeLa cell assays) and in vivo (Artemia salina test) even at the highest concentrations tested. Altogether, these findings position BcI-4 as a nature-inspired multitarget peptide with neuroprotective potential, combining reversible AChE inhibition, anti-amyloid, antioxidant, and MAO-B modulatory activities. BcI-4 represents a promising lead compound for the development of peptide-based therapeutics against AD.

阿尔茨海默病（AD）是一种多因素进行性神经退行性疾病，目前尚无有效的治疗方法。能够同时调节多种病理通路的多靶点定向配体（mtdl）的发展代表了解决其复杂病因的合理策略。在这项研究中，我们报道了BcI-4的分离、化学合成和功能表征，BcI-4是一种从阿根廷青蛙Boana cordobae皮肤分泌物中鉴定出的短阳离子肽。该肽对乙酰胆碱酯酶（AChE）表现出有效和可逆的抑制活性，重组人和电鳗AChE的IC₅₀值分别为1.10和0.9 μM，通过涉及外周阴离子位点（PAS）的非竞争机制起作用。BcI-4还能抑制乙酰胆碱诱导的β-淀粉样蛋白（Aβ）聚集，适度抑制单胺氧化酶B (MAO-B)，并具有抗氧化和金属螯合活性，包括抑制脂质过氧化。该肽保留了先前在cordobae粗提物中观察到的多功能药理特征，显著增强了对乙酰胆碱酯的效力和选择性。此外，BcI-4在体外（溶血和HeLa细胞试验）和体内（Artemia salina试验）即使在最高浓度下也无毒。总之，这些发现表明BcI-4是一种具有神经保护潜力的天然多靶点肽，具有可逆的AChE抑制、抗淀粉样蛋白、抗氧化和MAO-B调节活性。BcI-4是一种很有前途的先导化合物，可用于开发基于肽的阿尔茨海默病治疗药物。

{"title":"A nature-inspired peptide from the Boana cordobae frog as a potent and reversible AChE inhibitor with anti-amyloid and neuroprotective activities","authors":"Roque Spinelli , Ivan Sanchis , Milagros de Orellana , Maria Veronica Humpola , Álvaro Rietmann , Álvaro Sebastían Siano","doi":"10.1016/j.bioorg.2026.109566","DOIUrl":"10.1016/j.bioorg.2026.109566","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder for which no effective treatment currently exists. The development of multitarget-directed ligands (MTDLs) capable of simultaneously modulating several pathological pathways represents a rational strategy to address its complex etiology. In this study, we report the isolation, chemical synthesis, and functional characterization of BcI-4, a short cationic peptide identified from the skin secretion of the Argentinean frog <em>Boana cordobae</em>. The peptide exhibited potent and reversible inhibitory activity against acetylcholinesterase (AChE), with IC₅₀ values of 1.10 and 0.9 μM for recombinant human and <em>Electrophorus electricus</em> AChE, respectively, acting through a non-competitive mechanism involving the peripheral anionic site (PAS). BcI-4 also inhibited AChE-induced β-amyloid (Aβ) aggregation, showed modest monoamine oxidase B (MAO-B) inhibition, and displayed both antioxidant and metal-chelating activities, including inhibition of lipid peroxidation. The peptide retained the multifuctional pharmacological profile previously observed for the crude extract of <em>B. cordobae</em>, with significantly enhanced potency and selectivity toward AChE. Moreover, BcI-4 was non-toxic in vitro (hemolysis and HeLa cell assays) and in vivo (<em>Artemia salina</em> test) even at the highest concentrations tested. Altogether, these findings position BcI-4 as a nature-inspired multitarget peptide with neuroprotective potential, combining reversible AChE inhibition, anti-amyloid, antioxidant, and MAO-B modulatory activities. BcI-4 represents a promising lead compound for the development of peptide-based therapeutics against AD.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109566"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design-led synthesis and multidimensional evaluation of novel thiadiazoles as multitarget anti-Alzheimer agents: kinetics, DFT and in silico mapping. 设计主导合成和多维评价新型噻二唑作为多靶点抗阿尔茨海默病药物：动力学，DFT和硅制图。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-27 DOI: 10.1016/j.bioorg.2026.109564

Shoaib Khan, Tayyiaba Iqbal, Ijaz Ali, Kasim Sakran Abass, Maher Fathalla, Eman Alzahrani, Nasir Ud Din, Hamdy Kashtoh, Abdulrahman Almehizia

A novel series of thiadiazole-based Schiff base derivatives (1-16) was synthesized via an efficient multi-step route and characterized using ¹H NMR, ¹³C NMR, and HREI-MS. These compounds were evaluated for their anti-Alzheimer's and anti-urease potential. Among them, compounds 8 and 9 exhibited the most potent inhibition with IC₅₀ values of 6.60 ± 0.40 and 8.10 ± 0.10 μM for AChE, 7.40 ± 0.20 and 8.80 ± 0.40 μM for BChE, and 9.75 ± 1.60 and 10.15 ± 0.50 μM for urease, respectively. Donepezil and thiourea were used as standard inhibitors for comparative evaluation. Molecular docking and pharmacophore modeling supported the inhibitory potential of these compounds. ADMET profiling confirmed favorable drug-likeness and pharmacokinetic properties, while DFT and molecular dynamics simulations validated their stability and reactivity. These results highlight compounds 8 and 9 as promising leads for further development as multifunctional therapeutic agents against Alzheimer's disease and urease-related pathologies.

通过高效的多步法合成了一系列新的噻二唑基希夫碱衍生物（1-16），并利用1H NMR、13C NMR和HREI-MS对其进行了表征。对这些化合物的抗阿尔茨海默病和抗脲酶潜能进行了评价。其中，化合物8和9表现出最有效的抑制作用，其IC₅₀值对AChE为6.60±0.40和8.10±0.10 μM，对BChE为7.40±0.20和8.80±0.40 μM，对脲酶为9.75±1.60和10.15±0.50 μM。多奈哌齐和硫脲作为标准抑制剂进行比较评价。分子对接和药效团模型支持了这些化合物的抑制潜力。ADMET分析证实了其良好的药物相似性和药代动力学特性，而DFT和分子动力学模拟证实了其稳定性和反应性。这些结果突出了化合物8和9作为针对阿尔茨海默病和脲酶相关病理的多功能治疗剂的进一步开发前景。

{"title":"Design-led synthesis and multidimensional evaluation of novel thiadiazoles as multitarget anti-Alzheimer agents: kinetics, DFT and in silico mapping.","authors":"Shoaib Khan, Tayyiaba Iqbal, Ijaz Ali, Kasim Sakran Abass, Maher Fathalla, Eman Alzahrani, Nasir Ud Din, Hamdy Kashtoh, Abdulrahman Almehizia","doi":"10.1016/j.bioorg.2026.109564","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.109564","url":null,"abstract":"<p><p>A novel series of thiadiazole-based Schiff base derivatives (1-16) was synthesized via an efficient multi-step route and characterized using <sup>1</sup>H NMR, <sup>13</sup>C NMR, and HREI-MS. These compounds were evaluated for their anti-Alzheimer's and anti-urease potential. Among them, compounds 8 and 9 exhibited the most potent inhibition with IC₅₀ values of 6.60 ± 0.40 and 8.10 ± 0.10 μM for AChE, 7.40 ± 0.20 and 8.80 ± 0.40 μM for BChE, and 9.75 ± 1.60 and 10.15 ± 0.50 μM for urease, respectively. Donepezil and thiourea were used as standard inhibitors for comparative evaluation. Molecular docking and pharmacophore modeling supported the inhibitory potential of these compounds. ADMET profiling confirmed favorable drug-likeness and pharmacokinetic properties, while DFT and molecular dynamics simulations validated their stability and reactivity. These results highlight compounds 8 and 9 as promising leads for further development as multifunctional therapeutic agents against Alzheimer's disease and urease-related pathologies.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"109564"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel hydrazone-derived pyrazole-benzofuran compounds inhibit cancer cell growth by targeting MMPs, caspases, and PI3K/AKT/mTOR signaling pathway 新型腙衍生物吡唑苯并呋喃化合物通过靶向MMPs、半胱天冬酶和PI3K/AKT/mTOR信号通路抑制癌细胞生长

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-27 DOI: 10.1016/j.bioorg.2026.109568

Issam Ameziane El Hassani , Ahmet Altay , Esma Yeniçeri , Youness Boukharsa , Hamza Assila , Abdullah Yahya Abdullah Alzahrani , Sana Ben Moussa , M'’hammed Ansar , Khalid Karrouchi

In this research, a series of novel pyrazole-benzofuran hydrazone hybrids (3a-h) were designed, synthesis and evaluated for their anticancer potential. All hybrid pyrazole-benzofuran derivatives were purified and characterized by using ¹H NMR, ¹³C NMR, and ESI-HRMS analyses. Their cytotoxic potentials were evaluated against human lung carcinoma (A-549) and colorectal adenocarcinoma (HT-29) cell lines, and mouse fibroblast (3T3-L1) cells using XTT assay. The findings demonstrated that all compounds exhibited a dose-dependent anti-proliferative effect against the cancer cell lines under investigation. Compound 3d was particularly distinguished by its noteworthy IC₅₀ value of 0.28 μM and a selectivity index of 103.85 on A549 cells. Advanced mechanistic anticancer investigations employing flow cytometry revealed that compound 3d triggered apoptosis in A549 cells by inducing mitochondrial membrane disruption and activating multiple caspases. Furthermore, both flow cytometry and Western blot analysis showed that the 3d molecule significantly suppressed the PI3K/AKT/mTOR signaling pathway, which is vital for cellular proliferation. In summary, the findings suggest that compound 3d has the potential to be evaluated as a therapeutic agent for the treatment of lung cancer.

本研究设计、合成了一系列新型吡唑-苯并呋喃腙杂合物（3a-h），并对其抗癌潜力进行了评价。对所有杂化吡唑-苯并呋喃衍生物进行了纯化，并用1H NMR、13C NMR和ESI-HRMS对其进行了表征。采用XTT法评价其对人肺癌（A-549）、结直肠癌（HT-29）细胞系和小鼠成纤维细胞（3T3-L1）的细胞毒性。研究结果表明，所有化合物对所研究的癌细胞系都表现出剂量依赖性的抗增殖作用。化合物3d在A549细胞上的IC50值为0.28 μM，选择性指数为103.85。利用流式细胞术进行的先进的抗癌机制研究表明，化合物3d通过诱导线粒体膜破坏和激活多种半胱天蛋白酶来诱导A549细胞凋亡。此外，流式细胞术和Western blot分析显示，3d分子显著抑制PI3K/AKT/mTOR信号通路，该信号通路对细胞增殖至关重要。总之，研究结果表明，化合物3d有潜力被评估为治疗肺癌的治疗剂。

{"title":"Novel hydrazone-derived pyrazole-benzofuran compounds inhibit cancer cell growth by targeting MMPs, caspases, and PI3K/AKT/mTOR signaling pathway","authors":"Issam Ameziane El Hassani , Ahmet Altay , Esma Yeniçeri , Youness Boukharsa , Hamza Assila , Abdullah Yahya Abdullah Alzahrani , Sana Ben Moussa , M'’hammed Ansar , Khalid Karrouchi","doi":"10.1016/j.bioorg.2026.109568","DOIUrl":"10.1016/j.bioorg.2026.109568","url":null,"abstract":"<div><div>In this research, a series of novel pyrazole-benzofuran hydrazone hybrids (<strong>3a-h</strong>) were designed, synthesis and evaluated for their anticancer potential. All hybrid pyrazole-benzofuran derivatives were purified and characterized by using <sup>1</sup>H NMR, <sup>13</sup>C NMR, and ESI-HRMS analyses. Their cytotoxic potentials were evaluated against human lung carcinoma (A-549) and colorectal adenocarcinoma (HT-29) cell lines, and mouse fibroblast (3T3-L1) cells using XTT assay. The findings demonstrated that all compounds exhibited a dose-dependent anti-proliferative effect against the cancer cell lines under investigation. Compound <strong>3d</strong> was particularly distinguished by its noteworthy IC<sub>50</sub> value of 0.28 μM and a selectivity index of 103.85 on A549 cells. Advanced mechanistic anticancer investigations employing flow cytometry revealed that compound <strong>3d</strong> triggered apoptosis in A549 cells by inducing mitochondrial membrane disruption and activating multiple caspases. Furthermore, both flow cytometry and Western blot analysis showed that the <strong>3d</strong> molecule significantly suppressed the PI3K/AKT/mTOR signaling pathway, which is vital for cellular proliferation. In summary, the findings suggest that compound <strong>3d</strong> has the potential to be evaluated as a therapeutic agent for the treatment of lung cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109568"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic enzyme-oriented investigation of benzimidazole derivatives associated with kidney dysfunction: synthesis, molecular docking and in vivo toxicological evaluation 与肾功能障碍相关的苯并咪唑衍生物的机制酶导向研究：合成、分子对接和体内毒理学评价

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-26 DOI: 10.1016/j.bioorg.2026.109554

Sha Liu , Wenna Song , Qingliang Hu , Yibing Liang , Lifen Wang , Yebing Liu , Xinpan Chen , Liyan Wang , Dai Deng , Aihua Zhang , Yiming Guang , Xueqi Wang , Yongli Han , Hongdong Huang

A series of benzimidazole–oxadiazole–based Schiff base derivatives (1−10) was synthesized and evaluated as potential angiotensin-converting enzyme (ACE) inhibitors. The compounds were characterized using standard spectroscopic techniques and assessed for ACE inhibitory activity through in vitro enzyme assays, with ramipril used as the reference inhibitor. Several derivatives demonstrated significant inhibition, with analogue 8, bearing a trifluoromethyl (CF₃) substituent, exhibiting superior potency compared to ramipril. Molecular docking studies revealed favorable hydrogen bonding and hydrophobic interactions of the active compounds within the ACE catalytic pocket, supporting the observed inhibitory trends. Density functional theory (DFT) calculations provided insight into electronic features associated with enhanced activity, while in silico ADMET analysis suggested acceptable drug-likeness profiles. Furthermore, in vivo toxicity evaluation in rats indicated no observable adverse effects at the tested doses. Overall, the study identifies these benzimidazole–oxadiazole Schiff bases as promising ACE inhibitory scaffolds for further pharmacological optimization.

合成了一系列苯并咪唑-恶二唑基希夫碱衍生物（1−10），并对其作为潜在的血管紧张素转换酶（ACE）抑制剂进行了评价。采用标准光谱技术对化合物进行表征，并以雷米普利作为对照抑制剂，通过体外酶测定评估其ACE抑制活性。几种衍生物表现出明显的抑制作用，类似物8含有三氟甲基（CF₃）取代基，与雷米普利相比具有更好的效力。分子对接研究揭示了ACE催化袋内活性化合物的良好氢键和疏水相互作用，支持了观察到的抑制趋势。密度泛函理论（DFT）计算提供了与增强活性相关的电子特征的见解，而计算机ADMET分析则提出了可接受的药物相似谱。此外，在大鼠体内毒性评估表明，在测试剂量下没有观察到不良反应。总的来说，该研究确定了这些苯并咪唑-恶二唑希夫碱是有前途的ACE抑制支架，可以进一步进行药理学优化。

{"title":"Mechanistic enzyme-oriented investigation of benzimidazole derivatives associated with kidney dysfunction: synthesis, molecular docking and in vivo toxicological evaluation","authors":"Sha Liu , Wenna Song , Qingliang Hu , Yibing Liang , Lifen Wang , Yebing Liu , Xinpan Chen , Liyan Wang , Dai Deng , Aihua Zhang , Yiming Guang , Xueqi Wang , Yongli Han , Hongdong Huang","doi":"10.1016/j.bioorg.2026.109554","DOIUrl":"10.1016/j.bioorg.2026.109554","url":null,"abstract":"<div><div>A series of benzimidazole–oxadiazole–based Schiff base derivatives (1−10) was synthesized and evaluated as potential angiotensin-converting enzyme (ACE) inhibitors. The compounds were characterized using standard spectroscopic techniques and assessed for ACE inhibitory activity through in vitro enzyme assays, with ramipril used as the reference inhibitor. Several derivatives demonstrated significant inhibition, with analogue 8, bearing a trifluoromethyl (CF₃) substituent, exhibiting superior potency compared to ramipril. Molecular docking studies revealed favorable hydrogen bonding and hydrophobic interactions of the active compounds within the ACE catalytic pocket, supporting the observed inhibitory trends. Density functional theory (DFT) calculations provided insight into electronic features associated with enhanced activity, while in silico ADMET analysis suggested acceptable drug-likeness profiles. Furthermore, in vivo toxicity evaluation in rats indicated no observable adverse effects at the tested doses. Overall, the study identifies these benzimidazole–oxadiazole Schiff bases as promising ACE inhibitory scaffolds for further pharmacological optimization.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109554"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent advances in chemistry and bioactivity of decalin-containing natural products (2014–2025) 含十calin天然产物化学及生物活性研究进展（2014-2025）

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-26 DOI: 10.1016/j.bioorg.2026.109549

Yaqi Lu , Yuyao Feng , Miaoping Lin, Humu Lu, Xiaodong Jiang, Xinya Xu, Yonghong Liu, Xiaowei Luo

Decalin-containing natural products are a significant family of structurally diverse secondary metabolites harboring architecturally multifunctionalized substituents in the decalin core. These compounds are predominantly originated from microorganisms, especially fungi, by terpene or polyketide biosynthetic pathways. They were found with remarkable biological properties, mainly including antimicrobial, antitumor, and antiinflammatory properties. The continuous studies have significantly expanded the structural types and biological diversity of decalin-containing natural products. To provide a comprehensive understanding of recent advances in the chemistry and bioactivity of decalin-containing natural products, this review summarizes 532 new polyketide-type (77.4%) and isoprenoid-type decalins (22.6%) reported from both terrestrial and marine organisms between 2014 and 2025, along with their chemical synthesis, biosynthesis, and structure activity relationships. This review will shed light on further untapped potential pharmacological applications and drug discovery in human health based on decalin-containing natural products.

含十calin天然产物是一个重要的家族结构多样的次级代谢物，在十calin核心中含有结构上多功能的取代基。这些化合物主要来源于微生物，特别是真菌，通过萜烯或聚酮类生物合成途径。它们被发现具有显著的生物学特性，主要包括抗菌、抗肿瘤和抗炎特性。随着研究的不断深入，含十钙素天然产物的结构类型和生物多样性得到了极大的拓展。为了全面了解含十calin天然产物的化学和生物活性的最新进展，本文综述了2014 - 2025年间从陆地和海洋生物中报道的532种新型聚酮型（77.4%）和类异戊二烯型（22.6%）十calin，以及它们的化学合成、生物合成和构效关系。这一综述将进一步揭示含十calin天然产物在人类健康方面未开发的潜在药理应用和药物发现。

{"title":"Recent advances in chemistry and bioactivity of decalin-containing natural products (2014–2025)","authors":"Yaqi Lu , Yuyao Feng , Miaoping Lin, Humu Lu, Xiaodong Jiang, Xinya Xu, Yonghong Liu, Xiaowei Luo","doi":"10.1016/j.bioorg.2026.109549","DOIUrl":"10.1016/j.bioorg.2026.109549","url":null,"abstract":"<div><div>Decalin-containing natural products are a significant family of structurally diverse secondary metabolites harboring architecturally multifunctionalized substituents in the decalin core. These compounds are predominantly originated from microorganisms, especially fungi, by terpene or polyketide biosynthetic pathways. They were found with remarkable biological properties, mainly including antimicrobial, antitumor, and antiinflammatory properties. The continuous studies have significantly expanded the structural types and biological diversity of decalin-containing natural products. To provide a comprehensive understanding of recent advances in the chemistry and bioactivity of decalin-containing natural products, this review summarizes 532 new polyketide-type (77.4%) and isoprenoid-type decalins (22.6%) reported from both terrestrial and marine organisms between 2014 and 2025, along with their chemical synthesis, biosynthesis, and structure activity relationships. This review will shed light on further untapped potential pharmacological applications and drug discovery in human health based on decalin-containing natural products.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109549"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ATR inhibitors: from targeting the DNA damage response to exploiting synthetic lethality—A paradigm shift in Cancer therapy ATR抑制剂：从靶向DNA损伤反应到利用合成致死性——癌症治疗的范式转变

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-26 DOI: 10.1016/j.bioorg.2026.109538

Xin Zhou , Qi Qin , Huizhi Yao , Yuxing Fu , Linxiao Wang , Wufu Zhu , Qiaoli Lv

Ataxia Telangiectasia and Rad3-related (ATR) kinase is a central orchestrator of the DNA replication stress response and a primary target for exploiting synthetic lethality in DDR-deficient cancers. This review systematically explores the molecular biology of ATR and the medicinal chemistry evolution of its inhibitors. We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Furthermore, we critically examine the pharmacological limitations and developability hurdles associated with Proteolysis-Targeting Chimeras (PROTACs), while evaluating the progress of rational combination regimens in clinical trials. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.

共济失调毛细血管扩张和rad3相关（ATR）激酶是DNA复制应激反应的中心协调者，也是利用ddr缺陷癌症的合成致死率的主要靶点。本文系统地综述了ATR的分子生物学及其抑制剂的药物化学演变。我们提供了主要临床候选药物的结构-活性关系（SAR）的详细分析，包括berzosertib， ceralasertib和elimusertib，重点是战略性化学修饰，如支架跳跃和亚砜亚胺替代，以优化选择性和药物性。此外，我们批判性地研究了靶向蛋白水解嵌合体（PROTACs）的药理学局限性和可开发性障碍，同时评估了临床试验中合理联合方案的进展。关键挑战，特别是剂量限制性血液学毒性和获得性耐药，在寻找强大的预测性生物标志物的同时进行分析。通过综合当前的药理学和临床数据，本工作概述了下一代atr靶向精准医学的发展轨迹。

{"title":"ATR inhibitors: from targeting the DNA damage response to exploiting synthetic lethality—A paradigm shift in Cancer therapy","authors":"Xin Zhou , Qi Qin , Huizhi Yao , Yuxing Fu , Linxiao Wang , Wufu Zhu , Qiaoli Lv","doi":"10.1016/j.bioorg.2026.109538","DOIUrl":"10.1016/j.bioorg.2026.109538","url":null,"abstract":"<div><div>Ataxia Telangiectasia and Rad3-related (ATR) kinase is a central orchestrator of the DNA replication stress response and a primary target for exploiting synthetic lethality in DDR-deficient cancers. This review systematically explores the molecular biology of ATR and the medicinal chemistry evolution of its inhibitors. We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Furthermore, we critically examine the pharmacological limitations and developability hurdles associated with Proteolysis-Targeting Chimeras (PROTACs), while evaluating the progress of rational combination regimens in clinical trials. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109538"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in green technologies for biocatalytic synthesis of chiral compounds: from enzymatic catalysis to multidisciplinary collaborative innovation 手性化合物生物催化合成的绿色技术进展：从酶催化到多学科协同创新

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-26 DOI: 10.1016/j.bioorg.2026.109543

Hongyue Wei , Bing Liu , Ting Zhu , Yuchen Liu , Lijing Zhang , Ning Chen , Wenlan Li

Chiral compounds are highly valuable in pharmaceuticals and materials because of their distinct stereostructures. However, traditional synthesis methods often encounter difficulties, such as demanding reaction conditions and substantial pollution. Biosynthetic technologies, harnessing the intrinsic features of enzymatic catalysis—such as high stereoselectivity and environmental benignity—have established themselves as a pivotal strategy to surmount these traditional limitations. This article reviews recent advances in biocatalytic synthesis of chiral compounds. Key developments include enzyme engineering for precise chiral center formation—through modification of oxidoreductases and lyases, and design of bifunctional and artificial enzymes—as well as photo- and electro-enzymatic catalysis that merge energy-driven processes with biocatalysis for efficient synthesis under mild conditions. Microbial engineering using engineered Escherichia. coli and yeast enables scalable production of chiral compounds, including chiral sesquiterpenes (e.g., (-)-β-elemene, drimenol, albicanol), chiral alkaloid precursors (e.g., (-)-dehydrobrevianamide E), and other high-value chiral intermediates, via optimized metabolic pathways. Mechanistic studies on imine reductases and amino acid dehydrogenases support rational enzyme design. Current technologies exhibit green characteristics, yet confront challenges such as enzyme stability. Looking ahead, the integration of interdisciplinary technologies is expected to drive the intellectualization and sustainability of chiral synthesis technologies.

手性化合物因其独特的立体结构而在医药和材料领域具有很高的应用价值。然而，传统的合成方法往往会遇到反应条件苛刻、污染严重等困难。生物合成技术，利用酶催化的固有特性，如高立体选择性和环境亲和性，已经成为克服这些传统限制的关键策略。本文综述了手性化合物生物催化合成的最新进展。关键的发展包括通过修饰氧化还原酶和裂解酶来精确形成手性中心的酶工程，设计双功能酶和人工酶，以及光酶和电酶催化，将能量驱动过程与生物催化结合起来，在温和的条件下进行高效合成。利用工程大肠杆菌进行微生物工程。通过优化的代谢途径，大肠杆菌和酵母可以大规模生产手性化合物，包括手性倍半萜烯（如(-)-β-榄香烯、烯丙醇、白醇）、手性生物碱前体（如(-)-脱氢brevianamide E）和其他高价值的手性中间体。对亚胺还原酶和氨基酸脱氢酶的机理研究支持合理的酶设计。目前的技术表现出绿色特性，但面临着酶稳定性等挑战。展望未来，跨学科技术的融合有望推动手性合成技术的智能化和可持续性。

{"title":"Advances in green technologies for biocatalytic synthesis of chiral compounds: from enzymatic catalysis to multidisciplinary collaborative innovation","authors":"Hongyue Wei , Bing Liu , Ting Zhu , Yuchen Liu , Lijing Zhang , Ning Chen , Wenlan Li","doi":"10.1016/j.bioorg.2026.109543","DOIUrl":"10.1016/j.bioorg.2026.109543","url":null,"abstract":"<div><div>Chiral compounds are highly valuable in pharmaceuticals and materials because of their distinct stereostructures. However, traditional synthesis methods often encounter difficulties, such as demanding reaction conditions and substantial pollution. Biosynthetic technologies, harnessing the intrinsic features of enzymatic catalysis—such as high stereoselectivity and environmental benignity—have established themselves as a pivotal strategy to surmount these traditional limitations. This article reviews recent advances in biocatalytic synthesis of chiral compounds. Key developments include enzyme engineering for precise chiral center formation—through modification of oxidoreductases and lyases, and design of bifunctional and artificial enzymes—as well as photo- and electro-enzymatic catalysis that merge energy-driven processes with biocatalysis for efficient synthesis under mild conditions. Microbial engineering using engineered <em>Escherichia. coli</em> and yeast enables scalable production of chiral compounds, including chiral sesquiterpenes (e.g., (-)-β-elemene, drimenol, albicanol), chiral alkaloid precursors (e.g., (-)-dehydrobrevianamide E), and other high-value chiral intermediates, via optimized metabolic pathways. Mechanistic studies on imine reductases and amino acid dehydrogenases support rational enzyme design. Current technologies exhibit green characteristics, yet confront challenges such as enzyme stability. Looking ahead, the integration of interdisciplinary technologies is expected to drive the intellectualization and sustainability of chiral synthesis technologies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109543"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tunable triazole-based cholera toxin inhibitors: A QSAR-guided design and evaluation approach 可调的三唑基霍乱毒素抑制剂：qsar引导的设计和评估方法

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-26 DOI: 10.1016/j.bioorg.2026.109563

Huma Basheer , Chandra S. Azad , M. Samim , Imran A. Khan

Cholera toxin B subunit (CTB) is a validated target for anticholera therapeutics, but current inhibitors often suffer from synthetic complexity and limited tunability. This study aimed to develop a compact, tunable triazole scaffold exhibiting low-micromolar potency combined with high synthetic tractability. We applied a unified, QSAR-driven, multiscale computational-experimental workflow integrating molecular docking, induced fit docking (IFD), molecular dynamics (MD), QM/MM calculations, and descriptor-based QSAR modeling to prioritize a focused library of 44 N-sulfonyl triazole inhibitors.

QSAR modeling employed multiple regression techniques on molecular descriptors derived from E-Dragon software and quantum mechanical (QM/QM-MM) parameters. Models including Ordinary Linear Regression, LASSO, Ridge, Elastic Net, Random Forest, Support Vector Machine (SVM), and Gradient Boosting Machine (GBM) were developed. The best predictive performance was achieved by SVM (test R² = 0.79, RMSE = 0.49) and Random Forest (test R² = 0.77, RMSE = 0.52) on E-Dragon descriptors, while multiple linear regression yielded outstanding fits on QM descriptors (test R² up to 0.98, RMSE ∼0.14). Key molecular descriptors influencing activity included hydrogen bond donor count (ndonr), polarizability (AlogP), and topological indices (Jhetv).

Guided by these QSAR models, lead candidates were synthesized via regioselective Cu(I)/Ru-catalyzed click chemistry, with experimental CTB-ELISA screening confirming compound 5d as the most potent inhibitor (IC₅₀ = 11.78 ± 1.2 μM). Computational studies consistently supported these findings, demonstrating favorable binding energetics, dynamic adaptability, and optimal electronic complementarity for lead compounds.

This integrated strategy not only delivers a potent, synthetically accessible monovalent CTB inhibitor but also provides a rational, data-driven platform for rapid design and optimization for multivalent cholera toxin antagonists with improved efficacy.

霍乱毒素B亚单位（CTB）是抗霍乱治疗的有效靶点，但目前的抑制剂通常存在合成复杂性和有限的可调性。本研究旨在开发一种紧凑、可调的三唑支架，具有低微摩尔效力和高合成可追溯性。我们采用统一的、QSAR驱动的、多尺度计算-实验工作流程，集成了分子对接、诱导拟合对接（IFD）、分子动力学（MD）、QM/MM计算和基于描述符的QSAR建模，对44个n -磺酰基三唑抑制剂进行了优先排序。QSAR模型采用了基于E-Dragon软件的分子描述符和量子力学（QM/QM- mm）参数的多元回归技术。建立了普通线性回归、LASSO、Ridge、弹性网、随机森林、支持向量机（SVM）和梯度增强机（GBM）等模型。支持向量机（检验R2 = 0.79, RMSE = 0.49）和随机森林（检验R2 = 0.77, RMSE = 0.52）对E-Dragon描述符的预测效果最好，而多元线性回归对QM描述符的拟合效果很好（检验R2高达0.98,RMSE = 0.14）。影响活性的关键分子描述符包括氢键供体数（ndonr）、极化率（AlogP）和拓扑指数（Jhetv）。在这些QSAR模型的指导下，通过区域选择性Cu(I)/ ru催化的点击化学合成了候选先导物，实验CTB-ELISA筛选证实化合物5d是最有效的抑制剂（IC₅₀= 11.78±1.2 μM）。计算研究一致支持这些发现，证明了先导化合物具有良好的结合能、动态适应性和最佳的电子互补性。这种综合策略不仅提供了一种有效的、可合成的单价CTB抑制剂，而且还为快速设计和优化具有更高疗效的多价霍乱毒素拮抗剂提供了一个合理的、数据驱动的平台。

{"title":"Tunable triazole-based cholera toxin inhibitors: A QSAR-guided design and evaluation approach","authors":"Huma Basheer , Chandra S. Azad , M. Samim , Imran A. Khan","doi":"10.1016/j.bioorg.2026.109563","DOIUrl":"10.1016/j.bioorg.2026.109563","url":null,"abstract":"<div><div>Cholera toxin B subunit (CTB) is a validated target for anticholera therapeutics, but current inhibitors often suffer from synthetic complexity and limited tunability. This study aimed to develop a compact, tunable triazole scaffold exhibiting low-micromolar potency combined with high synthetic tractability. We applied a unified, QSAR-driven, multiscale computational-experimental workflow integrating molecular docking, induced fit docking (IFD), molecular dynamics (MD), QM/MM calculations, and descriptor-based QSAR modeling to prioritize a focused library of 44 N-sulfonyl triazole inhibitors.</div><div>QSAR modeling employed multiple regression techniques on molecular descriptors derived from <em>E</em>-Dragon software and quantum mechanical (QM/QM-MM) parameters. Models including Ordinary Linear Regression, LASSO, Ridge, Elastic Net, Random Forest, Support Vector Machine (SVM), and Gradient Boosting Machine (GBM) were developed. The best predictive performance was achieved by SVM (test R<sup>2</sup> = 0.79, RMSE = 0.49) and Random Forest (test R<sup>2</sup> = 0.77, RMSE = 0.52) on <em>E</em>-Dragon descriptors, while multiple linear regression yielded outstanding fits on QM descriptors (test R<sup>2</sup> up to 0.98, RMSE ∼0.14). Key molecular descriptors influencing activity included hydrogen bond donor count (ndonr), polarizability (AlogP), and topological indices (Jhetv).</div><div>Guided by these QSAR models, lead candidates were synthesized <em>via</em> regioselective Cu(I)/Ru-catalyzed click chemistry, with experimental CTB-ELISA screening confirming compound <strong>5d</strong> as the most potent inhibitor (IC₅₀ = 11.78 ± 1.2 μM). Computational studies consistently supported these findings, demonstrating favorable binding energetics, dynamic adaptability, and optimal electronic complementarity for lead compounds.</div><div>This integrated strategy not only delivers a potent, synthetically accessible monovalent CTB inhibitor but also provides a rational, data-driven platform for rapid design and optimization for multivalent cholera toxin antagonists with improved efficacy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109563"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, regioselective, time gated synthesis of novel benzo[d]imidazole analogues as potential quorum sensing inhibitors targeting LasR in Pseudomonas aeruginosa 新型苯并咪唑类似物作为铜绿假单胞菌激光感应抑制剂的设计、区域选择性、时间门控合成

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-26 DOI: 10.1016/j.bioorg.2026.109561

Esraa Z. Mohammed , Heba S. Rateb , Amira A. Helwa , Nourhan G. Naga , Mona E.M. Mabrouk , Ahmed B.M. Mehany , Hatem A. Abdel Aziz , Nehad M. El-Dydamony

The rapid emergence of antibiotic-resistant pathogens highlights the crucial need for alternate anti-infective strategies. Quorum sensing inhibition (QSI) offers compelling approaches to attenuate bacterial virulence while limiting the resistance. In this study, fourteen Benzo[d]imidazole derivatives were synthesized and proposed as potential LasR antagonists exhibiting quorum-sensing inhibitory activity. Among these, compounds 7f, 7 h, 11b, 11c, and 11f demonstrated a marked ability to suppress biofilm formation in P. aeruginosa by (83%, 87%, 84%, 87%, 86%), pyocyanin production (76%, 84%, 86%, 82%, 81%), and motility activity; swimming (90%, 86%, 91%, 88%, 90%), twitching (90%, 94%, 93%, 86%, 92%), respectively. Additionally, compounds 7f and 11c effectively inhibited LasR, with IC₅₀ values equal to 0.74 ± 0.005, 0.79 ± 0.001 μM, respectively. Moreover, a 200-ns molecular dynamics simulation (MDS) of the 7f analogue indicated its potential to disrupt the dimeric structure of the LasR protein, thereby confirming its inhibitory activity toward LasR. Collectively, these results establish benzo[d]imidazole scaffolds as promising leads for the development of next-generation quorum sensing modulators aimed at disarming bacterial pathogenicity and countering antimicrobial resistance.

抗生素耐药病原体的迅速出现凸显了对替代抗感染策略的迫切需要。群体感应抑制（QSI）提供了令人信服的方法来减弱细菌毒力，同时限制耐药性。在这项研究中，合成了14个苯并咪唑衍生物，并提出了作为具有群体感应抑制活性的潜在LasR拮抗剂。其中，化合物7f、7h、11b、11c和11f对铜绿假单胞菌生物膜的形成（83%、87%、84%、87%、86%）、pyocyanin的产生（76%、84%、86%、82%、81%）和运动活性具有显著的抑制作用；游泳（90%,86%,91%,88%,90%），抽搐（90%,94%,93%,86%,92%）。化合物7f和11c的IC50值分别为0.74±0.005、0.79±0.001 μM，对LasR有较好的抑制作用。此外，7f类似物的200-ns分子动力学模拟（MDS）表明其可能破坏LasR蛋白的二聚体结构，从而证实其对LasR的抑制活性。总的来说，这些结果表明苯并咪唑支架是开发下一代群体感应调节剂的有希望的线索，旨在解除细菌致病性和对抗抗菌素耐药性。

{"title":"Design, regioselective, time gated synthesis of novel benzo[d]imidazole analogues as potential quorum sensing inhibitors targeting LasR in Pseudomonas aeruginosa","authors":"Esraa Z. Mohammed , Heba S. Rateb , Amira A. Helwa , Nourhan G. Naga , Mona E.M. Mabrouk , Ahmed B.M. Mehany , Hatem A. Abdel Aziz , Nehad M. El-Dydamony","doi":"10.1016/j.bioorg.2026.109561","DOIUrl":"10.1016/j.bioorg.2026.109561","url":null,"abstract":"<div><div>The rapid emergence of antibiotic-resistant pathogens highlights the crucial need for alternate anti-infective strategies. Quorum sensing inhibition (QSI) offers compelling approaches to attenuate bacterial virulence while limiting the resistance. In this study, fourteen <strong>Benzo[<em>d</em>]imidazole</strong> derivatives were synthesized and proposed as potential LasR antagonists exhibiting quorum-sensing inhibitory activity. Among these, compounds <strong>7f</strong>, <strong>7</strong> <strong>h</strong>, <strong>11b, 11c</strong>, and <strong>11f</strong> demonstrated a marked ability to suppress biofilm formation in <em>P. aeruginosa</em> by (83%, 87%, 84%, 87%, 86%), pyocyanin production (76%, 84%, 86%, 82%, 81%), and motility activity; swimming (90%, 86%, 91%, 88%, 90%), twitching (90%, 94%, 93%, 86%, 92%), respectively. Additionally, compounds <strong>7f</strong> and <strong>11c</strong> effectively inhibited LasR, with IC<sub>50</sub> values equal to 0.74 ± 0.005, 0.79 ± 0.001 μM, respectively. Moreover, a 200-ns molecular dynamics simulation (MDS) of the <strong>7f</strong> analogue indicated its potential to disrupt the dimeric structure of the LasR protein, thereby confirming its inhibitory activity toward LasR. Collectively, these results establish <strong>benzo[<em>d</em>]imidazole</strong> scaffolds as promising leads for the development of next-generation quorum sensing modulators aimed at disarming bacterial pathogenicity and countering antimicrobial resistance.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109561"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Is it feasible for CDKs inhibitors to herald a new era in tackling the low sensitivity and drug resistance associated with PARP inhibitors? CDKs抑制剂在解决PARP抑制剂相关的低敏感性和耐药方面是否可行？

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-25 DOI: 10.1016/j.bioorg.2026.109546

Ya-Lan Wang , Wen-Zhe Nie , Feng-Zhi Lu , Jin-Ying Liu , Ji-Hang He , Ya-Mei Li , Xiaoting Li , Qing-Kun Shen

PARPi exerts synthetic lethality by exploiting homologous recombination repair (HRR) deficiencies in tumor cells, demonstrating breakthrough efficacy in the treatment of various cancers with BRCA mutations, and has thus become one of the cornerstone strategies in precision oncology. However, primary insensitivity and acquired resistance observed in clinical practice significantly limit its long-term therapeutic benefits. Cyclin-dependent kinases (CDKs), as critical regulators of cell cycle progression and DNA damage repair pathways, represent promising therapeutic targets for overcoming PARPi resistance and enhancing treatment sensitivity. Through modulation of HRR-related gene transcription, activation of cell cycle checkpoints, and regulation of pro-survival signaling pathways in tumors, CDKs play a pivotal role in mediating these effects.This article systematically reviews the core mechanisms underlying the synergistic interaction between CDK inhibitors (CDKi) and PARPi. From a translational perspective, multiple clinical trials have confirmed the safety and preliminary efficacy of this combination strategy in solid tumors, particularly demonstrating synergistic antitumor activity in settings of PARPi resistance or in tumors with intact HRR function. The combinatorial approach of CDKi and PARPi, through multi-dimensional mechanistic integration, holds strong potential as a key strategy to overcome PARPi resistance and expand the population of patients who can benefit from this class of therapies.

PARPi利用肿瘤细胞的同源重组修复（homologous recombination repair， HRR）缺陷发挥合成致死性，在治疗多种BRCA突变的癌症中显示出突破性疗效，成为精准肿瘤学的基石策略之一。然而，在临床实践中观察到的原发性不敏感和获得性耐药严重限制了其长期治疗效果。细胞周期蛋白依赖性激酶（CDKs）作为细胞周期进程和DNA损伤修复途径的关键调节因子，代表了克服PARPi耐药和提高治疗敏感性的有希望的治疗靶点。CDKs通过调节hrr相关基因转录、激活细胞周期检查点和调节促生存信号通路，在肿瘤中发挥关键作用。本文系统综述了CDK抑制剂（CDKi）和PARPi之间协同作用的核心机制。从转化的角度来看，多项临床试验已经证实了这种联合策略在实体肿瘤中的安全性和初步疗效，特别是在PARPi耐药或HRR功能完整的肿瘤中显示出协同抗肿瘤活性。CDKi和PARPi的组合方法，通过多维机制整合，具有强大的潜力，作为克服PARPi耐药的关键策略，并扩大可以从这类治疗中受益的患者群体。

{"title":"Is it feasible for CDKs inhibitors to herald a new era in tackling the low sensitivity and drug resistance associated with PARP inhibitors?","authors":"Ya-Lan Wang , Wen-Zhe Nie , Feng-Zhi Lu , Jin-Ying Liu , Ji-Hang He , Ya-Mei Li , Xiaoting Li , Qing-Kun Shen","doi":"10.1016/j.bioorg.2026.109546","DOIUrl":"10.1016/j.bioorg.2026.109546","url":null,"abstract":"<div><div>PARPi exerts synthetic lethality by exploiting homologous recombination repair (HRR) deficiencies in tumor cells, demonstrating breakthrough efficacy in the treatment of various cancers with BRCA mutations, and has thus become one of the cornerstone strategies in precision oncology. However, primary insensitivity and acquired resistance observed in clinical practice significantly limit its long-term therapeutic benefits. Cyclin-dependent kinases (CDKs), as critical regulators of cell cycle progression and DNA damage repair pathways, represent promising therapeutic targets for overcoming PARPi resistance and enhancing treatment sensitivity. Through modulation of HRR-related gene transcription, activation of cell cycle checkpoints, and regulation of pro-survival signaling pathways in tumors, CDKs play a pivotal role in mediating these effects.This article systematically reviews the core mechanisms underlying the synergistic interaction between CDK inhibitors (CDKi) and PARPi. From a translational perspective, multiple clinical trials have confirmed the safety and preliminary efficacy of this combination strategy in solid tumors, particularly demonstrating synergistic antitumor activity in settings of PARPi resistance or in tumors with intact HRR function. The combinatorial approach of CDKi and PARPi, through multi-dimensional mechanistic integration, holds strong potential as a key strategy to overcome PARPi resistance and expand the population of patients who can benefit from this class of therapies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109546"},"PeriodicalIF":4.7,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0