Bioorganic & Medicinal Chemistry Letters最新文献_第9页

Solid-phase supported direct 18F-radiofluorination of peptides 多肽的固相直接 18F 放射氟化。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130118

Eduardo F.A. Fernandes , Line B.S. Knudsen , Andreas Kjaer , Kristian Strømgaard , Matthias M. Herth

引用次数: 0

Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer 发现双PARP/NAMPT抑制剂治疗BRCA野生型三阴性乳腺癌。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130117

Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang

{"title":"Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer","authors":"Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang","doi":"10.1016/j.bmcl.2025.130117","DOIUrl":"10.1016/j.bmcl.2025.130117","url":null,"abstract":"<div><div>Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound <strong>13j</strong> with potent inhibitory activity against both PARP1 and NAMPT (IC<sub>50</sub> <em>=</em> 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, <strong>13j</strong> disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound <strong>13j</strong> is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130117"},"PeriodicalIF":2.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury 用香维罗优化氯贝酸酯，得到一种低肝损伤的新型降血脂化合物。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-29 DOI: 10.1016/j.bmcl.2025.130116

Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie

{"title":"Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury","authors":"Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie","doi":"10.1016/j.bmcl.2025.130116","DOIUrl":"10.1016/j.bmcl.2025.130116","url":null,"abstract":"<div><div>The hepatic injury caused by clofibrate (CF) is strongly associated with oxidative stress and inflammation. This study aims to develop a hypolipidemic compound that possesses antioxidant, anti-inflammatory properties and reduces liver injury. Carvacrol-clofibrate (CF-Carvacrol) was synthesized by optimizing the structure of CF by carvacrol. CF-Carvacrol showed significant lipid-lowering effects in hyperlipidemic mouse models induced by Triton WR 1339. The molecular docking results showed that CF-Carvacrol has a good affinity for PPAR-α. The liver injury study showed that CF-Carvacrol had significantly lower liver injury compared to CF. Manifested as a significant decrease in liver weight and liver coefficient (<em>P <</em> 0.01), as well as a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) (<em>P <</em> 0.01). Histopathology of liver tissue showed that the necrosis of liver cells, cytoplasmic looseness, nuclear degeneration, and infiltration of inflammatory cells were significantly reduced in the CF-Carvacrol group. CF-Carvacrol can significantly up-regulate the expression of Nrf2 and HO-1 in liver (<em>P <</em> 0.05, <em>P <</em> 0.01). The expression of inflammatory factors TNF-α and IL-6 in the liver was significantly down-regulation (<em>P <</em> 0.05, <em>P <</em> 0.01). The levels of superoxide dismutase (SOD) and glutathione (GSH) significantly increased (<em>P <</em> 0.05, <em>P <</em> 0.01), while the content of malondialdehyde (MDA) in lipid peroxidation significantly decreased (<em>P <</em> 0.01). These results revealed that CF-Carvacrol has significant hypolipidemic activity and mild liver injury, and may exert antioxidant and anti-inflammatory activity by activating the Nrf2/HO-1 signaling pathway to reduce liver injury.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130116"},"PeriodicalIF":2.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synthesis and evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates KX-01类似物的合成与评价及抗体-药物偶联物的连接点探索。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130114

Yeju Oh , Da Eun An , Jaebeom Park , Byumseok Koh , Kyung-Jin Cho , Hongjun Jeon

引用次数: 0

A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus 苯并恶唑脲抑制VraS并增强抗万古霉素中耐药金黄色葡萄球菌的抗菌剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130113

Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar

{"title":"A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus","authors":"Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar","doi":"10.1016/j.bmcl.2025.130113","DOIUrl":"10.1016/j.bmcl.2025.130113","url":null,"abstract":"<div><div>Vancomycin intermediate-resistant <em>Staphylococcus aureus</em> (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical <strong><em>1</em></strong>) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of <strong><em>1</em></strong> enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. <strong><em>1</em></strong> shows ∼30 % inhibition of ATPase activity in VraS and reduces <em>vra</em> gene auto-upregulation typical upon vancomycin exposure. Therefore, <strong><em>1</em></strong> inhibits VraS to block normal <em>vra</em> operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests <strong><em>1</em></strong> does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130113"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Derivatization of ophiobolin A and cytotoxicity toward breast and glioblastoma cancer stem cells: Varying the ketone and unsaturated aldehyde moieties 蛇血蛋白A的衍生化和对乳腺癌和胶质母细胞瘤癌症干细胞的细胞毒性：改变酮和不饱和醛部分。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130112

Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo

{"title":"Derivatization of ophiobolin A and cytotoxicity toward breast and glioblastoma cancer stem cells: Varying the ketone and unsaturated aldehyde moieties","authors":"Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo","doi":"10.1016/j.bmcl.2025.130112","DOIUrl":"10.1016/j.bmcl.2025.130112","url":null,"abstract":"<div><div>To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT<sup>+</sup>) cell line.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130112"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Nucleoside antiviral agents with atypical structures and new targets 具有非典型结构和新靶点的核苷类抗病毒药物。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130110

Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan

引用次数: 0

Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor 新型叔二芳乙胺作为kappa阿片受体的功能选择性激动剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-24 DOI: 10.1016/j.bmcl.2025.130111

Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen

{"title":"Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor","authors":"Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen","doi":"10.1016/j.bmcl.2025.130111","DOIUrl":"10.1016/j.bmcl.2025.130111","url":null,"abstract":"<div><div>Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus <em>β</em>-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure–activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound <strong>39</strong>, a potent activator of G-protein signaling (GTPγS EC<sub>50</sub> = 14 nM, 83 % <em>E</em><sub>max</sub>) that did not elicit a <em>β</em>-arrestin-2 recruitment functional response (<em>E</em><sub>max</sub> < 10 %). Compound <strong>39</strong> demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound <strong>39</strong> exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (<em>K</em><sub>i</sub>) assays. These findings highlight compound <strong>39</strong> and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130111"},"PeriodicalIF":2.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis 新型抗结核分枝杆菌的含异恶唑噻吩化合物。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-23 DOI: 10.1016/j.bmcl.2025.130108

Gabrielle Martinez, Kirsten Tolentino, Paridhi Sukheja, Jasmine Webb, Case W. McNamara, Arnab K. Chatterjee, Baiyuan Yang

引用次数: 0

Potent HIV‑1 protease inhibitors containing oxabicyclo octanol-derived P2-ligands: Design, synthesis, and X‑ray structural studies of inhibitor-HIV-1 protease complexes

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-21 DOI: 10.1016/j.bmcl.2025.130109

Arun K. Ghosh , Monika Yadav , Ashish Sharma , Megan Johnson , Ajay K. Ghosh , Rangu Prasad , Masayuki Amano , Oksana Gerlits , Andrey Kovalevsky , Hiroaki Mitsuya

引用次数: 0