Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第6页

Natural product as a lead for impairing mitochondrial respiration in cancer cells. 天然产物作为损害线粒体呼吸在癌细胞中的铅。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-27 DOI: 10.1080/14756366.2025.2465575

Agnieszka Pyrczak-Felczykowska, Anna-Karina Kaczorowska, Artur Giełdoń, Alicja Braczko, Ryszard T Smoleński, Jędrzej Antosiewicz, Tristan A Reekie, Anna Herman-Antosiewicz

{"title":"Natural product as a lead for impairing mitochondrial respiration in cancer cells.","authors":"Agnieszka Pyrczak-Felczykowska, Anna-Karina Kaczorowska, Artur Giełdoń, Alicja Braczko, Ryszard T Smoleński, Jędrzej Antosiewicz, Tristan A Reekie, Anna Herman-Antosiewicz","doi":"10.1080/14756366.2025.2465575","DOIUrl":"10.1080/14756366.2025.2465575","url":null,"abstract":"The impact of the isoxazole derivative of usnic acid, ISOXUS (formerly known as 2b) on cancer and non-cancerous cell metabolism was investigated. ISOXUS significantly reduced the utilisation of most metabolic substrates that produce NADH or FADH2, mitochondrial electron flow and oxygen consumption rate (OCR) in MCF-7 breast cancer cells in contrast to HB2 normal epithelial cells. Molecular docking revealed that ISOXUS inhibits mitochondrial respiratory chain complex II, which was confirmed experimentally. Disturbance of electron flow in MCF-7 cells resulted in increased reactive oxygen species (ROS) production. They appeared crucial for ISOXUS-induced cancer cell vacuolization and a drop in survival as an antioxidant, α-tocopherol, protected against these processes. These findings indicate that ISOXUS is a metabolic inhibitor that targets mitochondrial complex II in breast cancer cells resulting in diminished ATP production and increased ROS formation which translates into reduced cell viability.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2465575"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation. 5,6 -二氢- 8h -异喹啉[1,2 -b]喹唑啉-8- 1衍生物作为抑制巨噬细胞源性泡沫细胞形成的新型非脂源性ABCA1上调调节剂的合成和评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-26 DOI: 10.1080/14756366.2025.2470310

Changhuan Yang, Lin Chen, Yanmei Jiang, Demeng Sun, Yun Hu

{"title":"Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation.","authors":"Changhuan Yang, Lin Chen, Yanmei Jiang, Demeng Sun, Yun Hu","doi":"10.1080/14756366.2025.2470310","DOIUrl":"10.1080/14756366.2025.2470310","url":null,"abstract":"Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate ABCA1 expression. The structure-activity relationship was explored and summarised. Among the 28 derivatives, compound 3 exhibited the most potent activity in activating the ABCA1 promoter (2.50-fold), significantly up-regulating both ABCA1 mRNA and protein levels in RAW264.7 macrophage cells. Mechanism studies revealed that compound 3 acted by targeting the LXR-involved pathway. In a foam cell model, compound 3 reduced ox-LDL-induced lipid accumulation and thereby inhibited foam cell formation. Moreover, compared to the LXR agonist T0901317, compound 3 led to minimal accumulation of unwanted lipids and triglycerides in HepG2 cells. With little cytotoxicity towards all the tested cell lines, compound 3 holds promise as a novel potential anti-atherogenic agent for further exploration.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2470310"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D. A、C和D类丝氨酸β-内酰胺酶底物结合袋的结构比较。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2024-12-23 DOI: 10.1080/14756366.2024.2435365

Hyeonmin Lee, Hyunjae Park, Kiwoong Kwak, Chae-Eun Lee, Jiwon Yun, Donghyun Lee, Jung Hun Lee, Sang Hee Lee, Lin-Woo Kang

{"title":"Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.","authors":"Hyeonmin Lee, Hyunjae Park, Kiwoong Kwak, Chae-Eun Lee, Jiwon Yun, Donghyun Lee, Jung Hun Lee, Sang Hee Lee, Lin-Woo Kang","doi":"10.1080/14756366.2024.2435365","DOIUrl":"https://doi.org/10.1080/14756366.2024.2435365","url":null,"abstract":"β-lactams have been the most successful antibiotics, but the rise of multi-drug resistant (MDR) bacteria threatens their effectiveness. Serine β-lactamases (SBLs), among the most common causes of resistance, are classified as A, C, and D, with numerous variants complicating structural and substrate spectrum comparisons. This study compares representative SBLs of these classes, focusing on the substrate-binding pocket (SBP). SBP is kidney bean-shaped on the indented surface, formed mainly by loops L1, L2, and L3, and an additional loop Lc in class C. β-lactams bind in a conserved orientation, with the β-lactam ring towards L2 and additional rings towards the space between L1 and L3. Structural comparison shows each class has distinct SBP structures, but subclasses share a conserved scaffold. The SBP structure, accommodating complimentary β-lactams, determines the substrate spectrum of SBLs. The systematic comparison of SBLs, including structural compatibility between β-lactams and SBPs, will help understand their substrate spectrum.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2435365"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877318","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

Discovery and development of steroidal enzyme inhibitors as anti-cancer drugs: state-of-the-art and future perspectives. 甾体酶抑制剂作为抗癌药物的发现和发展：最新进展和未来展望。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-04-02 DOI: 10.1080/14756366.2025.2483818

Bruno Cerra, Antimo Gioiello

{"title":"Discovery and development of steroidal enzyme inhibitors as anti-cancer drugs: state-of-the-art and future perspectives.","authors":"Bruno Cerra, Antimo Gioiello","doi":"10.1080/14756366.2025.2483818","DOIUrl":"10.1080/14756366.2025.2483818","url":null,"abstract":"Steroidal compounds have emerged as effective therapeutic agents in oncology. Beyond natural-occurring and synthetic steroids that act as cytotoxic anti-tumoral agents, steroidal derivatives can be designed to mime the endogenous substrates of key metabolic enzymes in steroidogenesis, thus reducing the circulating levels of relevant oestrogenic and androgenic hormones responsible for cancer survival and proliferation. Therefore, enzyme inhibition represents an intriguing endocrine approach for the treatment of hormone-dependent tumours, such as breast and prostate cancer, with well-known approved drugs and several pre-clinical and clinical candidates under investigation. This review summarises the key advancements over the past decade (2014-2024) in the development of steroidal enzyme inhibitors endowed with anticancer activity, illustrating their mechanisms of action, therapeutic potential, drug design approaches, and current clinical applications. Furthermore, we discuss challenges related to drug resistance, off-target effects, and future strategies to optimise their efficacy in oncology.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2483818"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring structure-activity relationships of pyrrolyl diketo acid derivatives as non-nucleoside inhibitors of terminal deoxynucleotidyl transferase enzyme. 探讨吡咯酰二酮酸衍生物作为末端脱氧核苷酸转移酶非核苷类抑制剂的构效关系。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-09 DOI: 10.1080/14756366.2025.2496782

Valentina Noemi Madia, Nadia Garibaldi, Davide Ialongo, Elisa Patacchini, Valeria Tudino, Giuseppe Ruggieri, Laura Zarbo, Emanuele Cara, Antonio Coluccia, Marco Artico, Luigi Scipione, Antonella Messore, Francesco Saccoliti, Elisa Mentegari, Giovanni Maga, Roberto Di Santo, Emmanuele Crespan, Roberta Costi

{"title":"Exploring structure-activity relationships of pyrrolyl diketo acid derivatives as non-nucleoside inhibitors of terminal deoxynucleotidyl transferase enzyme.","authors":"Valentina Noemi Madia, Nadia Garibaldi, Davide Ialongo, Elisa Patacchini, Valeria Tudino, Giuseppe Ruggieri, Laura Zarbo, Emanuele Cara, Antonio Coluccia, Marco Artico, Luigi Scipione, Antonella Messore, Francesco Saccoliti, Elisa Mentegari, Giovanni Maga, Roberto Di Santo, Emmanuele Crespan, Roberta Costi","doi":"10.1080/14756366.2025.2496782","DOIUrl":"10.1080/14756366.2025.2496782","url":null,"abstract":"Terminal deoxynucleotidyl transferase (TdT) is overexpressed in some cancer types, where it drives the mutagenic repair of double strand breaks through non canonical non-homologous end joining pathway. The TdT enzyme belongs to the X family of polymerases, together with the DNA polymerase λ (pol λ) and β (pol β). However, TdT exclusively displays template-independent nucleotide polymerisation. Pursuing our studies in developing TdT inhibitors, herein we deepened the structure-activity relationships of new structural analogues of our previously identified hit compounds. The diketo hexenoic acid derivatives here analysed showed high selectivity towards TdT and inhibition potencies spanning from the low micromolar range to the nanomolar. Docking studies highlighted the chemical features involved in the TdT binding, well contributing to the rationalisation of the structural requirements needed for the enzymatic inhibition.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2496782"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors. 基于细胞内生物发光共振能量转移（BRET）的检测发现 Ceritinib 和 CA-074 是 SARS-CoV-2 类木瓜蛋白酶抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-20 DOI: 10.1080/14756366.2024.2387417

Mei Li, Zhu-Chun Bei, Yongtian Yuan, Baogang Wang, Dongna Zhang, Likun Xu, Liangliang Zhao, Qin Xu, Yabin Song

{"title":"In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors.","authors":"Mei Li, Zhu-Chun Bei, Yongtian Yuan, Baogang Wang, Dongna Zhang, Likun Xu, Liangliang Zhao, Qin Xu, Yabin Song","doi":"10.1080/14756366.2024.2387417","DOIUrl":"10.1080/14756366.2024.2387417","url":null,"abstract":"Papain-like protease (PLpro) is an attractive anti-coronavirus target. The development of PLpro inhibitors, however, is hampered by the limitations of the existing PLpro assay and the scarcity of validated active compounds. We developed a novel in-cell PLpro assay based on BRET and used it to evaluate and discover SARS-CoV-2 PLpro inhibitors. The developed assay demonstrated remarkable sensitivity for detecting the reduction of intracellular PLpro activity while presenting high reliability and performance for inhibitor evaluation and high-throughput screening. Using this assay, three protease inhibitors were identified as novel PLpro inhibitors that are structurally disparate from those previously known. Subsequent enzymatic assays and ligand-protein interaction analysis based on molecular docking revealed that ceritinib directly inhibited PLpro, showing high geometric complementarity with the substrate-binding pocket in PLpro, whereas CA-074 methyl ester underwent intracellular hydrolysis, exposing a free carboxyhydroxyl group essential for hydrogen bonding with G266 in the BL2 groove, resulting in PLpro inhibition.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2387417"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors. 作为 ASK1 抑制剂的喹喔啉衍生物的合成和生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-21 DOI: 10.1080/14756366.2024.2414382

Xiaorui Han, Pingping Lan, Qianfeng Chen, Hua Liu, Zhongwen Chen, Tiantian Wang, Zengtao Wang

引用次数: 0

Vitamin B6 inhibits activity of Helicobacter pylori adenylosuccinate synthetase and growth of reference and clinical, antibiotic-resistant H. pylori strains. 维生素 B6 可抑制幽门螺旋杆菌腺苷琥珀酸合成酶的活性以及参考菌株和临床抗生素耐药幽门螺旋杆菌菌株的生长。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-16 DOI: 10.1080/14756366.2024.2372734

Marta Ilona Wojtyś, Weronika Maksymiuk, Marta Narczyk, Ante Bubić, Ivana Leščić Ašler, Paweł Krzyżek, Grażyna Gościniak, Elżbieta Katarzyna Jagusztyn-Krynicka, Agnieszka Bzowska

{"title":"Vitamin B6 inhibits activity of Helicobacter pylori adenylosuccinate synthetase and growth of reference and clinical, antibiotic-resistant H. pylori strains.","authors":"Marta Ilona Wojtyś, Weronika Maksymiuk, Marta Narczyk, Ante Bubić, Ivana Leščić Ašler, Paweł Krzyżek, Grażyna Gościniak, Elżbieta Katarzyna Jagusztyn-Krynicka, Agnieszka Bzowska","doi":"10.1080/14756366.2024.2372734","DOIUrl":"10.1080/14756366.2024.2372734","url":null,"abstract":"The current therapies against gastric pathogen Helicobacter pylori are ineffective in over 20% of patients. Enzymes belonging to the purine salvage pathway are considered as novel drug targets in this pathogen. Therefore, the main aim of the current study was to determine the antibacterial activity of pyridoxal 5'-phosphate (PLP), an active form of vitamin B6, against reference and clinical strains of H. pylori. Using a broad set of microbiological, physicochemical (UV absorption, LC-MS, X-ray analysis) and in silico experiments, we were able to prove that PLP inhibits adenylosuccinate synthetase (AdSS) from H. pylori by the competition with GTP (IC50eq ∼30 nM). This behaviour was attributed to formation of a Schiff base with a lysine residue (a covalent bond with Lys322 in the GTP binding site of AdSS) and was potentiated by the presence of vitamin C. This antibacterial activity of PLP gives hope for its future use against H. pylori.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2372734"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease. 作为选择性丁酰胆碱酯酶抑制剂治疗阿尔茨海默病的新型抗神经炎吡喃酮-氨基甲酸酯衍生物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-02-16 DOI: 10.1080/14756366.2024.2313682

Chuanyu Yu, Xueyan Liu, Bingxiang Ma, Jiexin Xu, Yiquan Chen, Chaoxian Dai, Huaping Peng, Daijun Zha

{"title":"Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease.","authors":"Chuanyu Yu, Xueyan Liu, Bingxiang Ma, Jiexin Xu, Yiquan Chen, Chaoxian Dai, Huaping Peng, Daijun Zha","doi":"10.1080/14756366.2024.2313682","DOIUrl":"10.1080/14756366.2024.2313682","url":null,"abstract":"Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2313682"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10878344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139741200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction. 更正。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-07-29 DOI: 10.1080/14756366.2024.2374156

引用次数: 0