Bioorganic & Medicinal Chemistry Letters最新文献_第4页

Discovery of novel inhibitors for malate synthase of Mycobacterium Tuberculosis from natural products 从天然产物中发现新的结核分枝杆菌苹果酸合成酶抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-03 DOI: 10.1016/j.bmcl.2025.130217

Zhili Wu , Yuchen Wu , Yanhong Niu , Qianfang Hu , Qihua Jiang , Lingbing Liao , Guorong Qi , Haoyang Lan , Xiaolan Yang

{"title":"Discovery of novel inhibitors for malate synthase of Mycobacterium Tuberculosis from natural products","authors":"Zhili Wu , Yuchen Wu , Yanhong Niu , Qianfang Hu , Qihua Jiang , Lingbing Liao , Guorong Qi , Haoyang Lan , Xiaolan Yang","doi":"10.1016/j.bmcl.2025.130217","DOIUrl":"10.1016/j.bmcl.2025.130217","url":null,"abstract":"<div><div>Tuberculosis (TB) caused by <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) remains a global public health threat, particularly due to dormant <em>Mtb</em>, which necessitates prolonged drug treatment. <em>Mycobacterium tuberculosis</em> malate synthase (<em>Mtb</em>MS) is a key rate-limiting enzyme in the glyoxylate shunt, essential for the survival of dormant <em>Mtb</em> but absent in the host. Using target-based virtual screening and biochemical approaches, we identified novel natural inhibitors of <em>Mtb</em>MS. Molecular docking by Schrödinger and subsequent manual selection identified 11 compounds as potential inhibitors. Molecular dynamics (MD) simulations and binding-free energy analysis (MM/GBSA) demonstrated high stability and binding affinity of <em>Mtb</em>MS with Nordihydroguaiaretic Acids (NDGA) and Meso-NDGA. NDGA and Meso-NDGA by inhibition experiment exhibited half-maximal inhibitory concentrations (IC<sub>50</sub>) against <em>Mtb</em>MS at 1.10 ± 0.01 μM and 14.29 ± 0.95 μM and by Isothermal Titration Calorimetry (ITC) showed binding constants (<em>K</em><sub>d</sub>) of 5.66 μM and 34.90 μM, respectively. Their minimum inhibitory concentrations (MIC) against <em>Mtb</em> H37Rv were 60.47 μg/mL and 30.24 μg/mL, respectively. In conclusion, natural products NDGA and Meso-NDGA are potent inhibitors of <em>Mtb</em>MS and represent promising new scaffolds for combating dormant <em>Mtb</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130217"},"PeriodicalIF":2.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787442","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

DNA binding studies of abietane diterpenes natural products using isothermal titration calorimetry, circular dichroism, fluorescence and gel assays 用等温滴定量热法、圆二色法、荧光法和凝胶法研究阿比烷二萜天然产物的DNA结合。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-03 DOI: 10.1016/j.bmcl.2025.130216

Ruel E. McKnight , Gavin S. Gullickson , Benjamin Kasper , Kevin Siegenthaler , Duanne A.C. Biggs , Roy B. Porter

{"title":"DNA binding studies of abietane diterpenes natural products using isothermal titration calorimetry, circular dichroism, fluorescence and gel assays","authors":"Ruel E. McKnight , Gavin S. Gullickson , Benjamin Kasper , Kevin Siegenthaler , Duanne A.C. Biggs , Roy B. Porter","doi":"10.1016/j.bmcl.2025.130216","DOIUrl":"10.1016/j.bmcl.2025.130216","url":null,"abstract":"<div><div>A group of four structurally related abietane diterpenes (including royleanone and 7-acetoxy-horminone) were investigated for their DNA binding capabilities using isothermal titration calorimetry (ITC), circular dichroism (CD) and fluorescence displacement spectroscopy, and a topoisomerase DNA-unwinding assay. Both ITC and CD spectroscopy data indicate that the abietane diterpenes of this study exhibit strong binding to DNA, likely preferring a DNA-groove binding mode. Binding constants (<em>K</em>) were found to be in the order of 10<sup>6–8</sup> M<sup>−1</sup> and were strongly enthalpically driven. The binding of all compounds to DNA was accompanied by large negative enthalpy changes (more than −20 kcal/mol) and negative entropy changes. The substituent at the 7th position of the abietane ring system was important in determining both the magnitude of binding and the propensity to stack within their DNA binding sites, with derivatives 7-one/ene > 7-OAc/H. This is significant given the reports that the identity of the substituent at position-7 is a strong determinant for bioactivity. Although the specific CD data observed was compound-dependent, most showed strong signal perturbations around one or both of the DNA signature wavelengths (245 and 280 nm). However, we do not attribute these perturbations to DNA intercalation. Compounds that were capable of self-stacking (i.e., 7-ene and 7-one) were also able to elicit very strong positively induced CD signal (ICD) around 330 nm, as well as perturbations at higher wavelengths. Additionally, topoisomerase DNA-unwinding and ethidium fluorescence displacement assays were used to corroborate the DNA binding mode, which was found to be consistent with the abietane diterpene compounds adopting a non-intercalative DNA binding mode.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130216"},"PeriodicalIF":2.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787443","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

Aptamer-modified GSH-degradable honokiol polyprodrug nanoparticles for ovarian cancer-specific targeting therapy 用于卵巢癌特异性靶向治疗的适体修饰的gsh可降解的厚朴酚聚前药纳米颗粒。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-01 DOI: 10.1016/j.bmcl.2025.130215

Chunhua Guo, Xiaowei Cheng, Yuxing Yang, Lijuan Wang, Wenfang Wang, Liping Shao

{"title":"Aptamer-modified GSH-degradable honokiol polyprodrug nanoparticles for ovarian cancer-specific targeting therapy","authors":"Chunhua Guo, Xiaowei Cheng, Yuxing Yang, Lijuan Wang, Wenfang Wang, Liping Shao","doi":"10.1016/j.bmcl.2025.130215","DOIUrl":"10.1016/j.bmcl.2025.130215","url":null,"abstract":"<div><div>Honokiol (HK) is a polyphenol isolated from the Magnolia genus, a component of traditional Chinese herbal medicine, which can effectively suppress the growth of various tumors, including ovarian cancer. However, its low water solubility and lack of tumor-targeting ability have greatly hindered the clinical application of HK. Herein, a glutathione (GSH)-sensitive HK polyprodrug was prepared using HK as the backbone. An EpCAM-specific aptamer and poly(ethylene glycol) (PEG) were then conjugated to the HK polyprodrug, and the resulting polyprodrug was assembled into nanoparticles (NPs) in water. The HK polyprodrug-formed NPs achieved high drug loading and GSH-responsive drug release. Moreover, after optimization, HK polyprodrug NPs (A/P-PHK NP40), formed by aptamer-modified and PEG-modified prodrug at a feed molar ratio of 2: 3, exhibited the highest ability to target EpCAM-overexpressing ovarian cancer cells. A/P-PHK NP40 also demonstrated a greater cell growth inhibition effect in ovarian cancer cells compared to free HK and control HK NPs. All in all, this work reported a novel strategy for HK delivery based on microenvironment responsiveness polyprodrug, which provided a potential method for ovarian cancer targeting therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130215"},"PeriodicalIF":2.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778529","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

Discovery of novel pyridine skeleton derivatives as potent CLK2/3 inhibitors 新型吡啶骨架衍生物作为CLK2/3抑制剂的发现。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-29 DOI: 10.1016/j.bmcl.2025.130212

Jie Wei , Guochuang Zheng , Tingting Yu , Qi Liu , Wenying Yu , Cheng Jiang , Xu Quan

{"title":"Discovery of novel pyridine skeleton derivatives as potent CLK2/3 inhibitors","authors":"Jie Wei , Guochuang Zheng , Tingting Yu , Qi Liu , Wenying Yu , Cheng Jiang , Xu Quan","doi":"10.1016/j.bmcl.2025.130212","DOIUrl":"10.1016/j.bmcl.2025.130212","url":null,"abstract":"<div><div>The CLK family plays a crucial role in regulating the transcript splicing, catalyzing the molecular mechanism of spliceosomes. It also regulates the activity or expression of non-spliced proteins by phosphorylating SR proteins. Hence, CLKs are promising therapeutic targets for a variety of diseases, especially in tumors. Several small molecule CLK2/3 inhibitors were under the clinical studies, while most of these molecule possessed N-containing bicyclic heteroaryl as the skeleton. The goal of this work was to introduce a novel skeleton as well as provide structure diversity to the development of CLK2/3 inhibitors. Herein, a series of pyridine derivatives (<strong>5a-5h</strong>, <strong>6a-6e</strong>, and <strong>7a-7g</strong>) were designed, synthesized and evaluated. Among them, compound <strong>7c</strong> was identified to have good inhibitory activities against both CLK2/3 and proliferation of SW480 tumor cell. Additionally, pharmacokinetic study in mice as well as the stability assay were performed to investigate the druggability of <strong>7c</strong>. The good in vitro activity and promising pharmacokinetic properties indicated that the <strong>7c</strong> was a reliable lead compound for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130212"},"PeriodicalIF":2.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750571","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 biological evaluation of novel 4-Arylaminoquinolines derivatives as EGFR/HDAC inhibitors 新型4-芳基喹啉类EGFR/HDAC抑制剂的合成及生物学评价

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-29 DOI: 10.1016/j.bmcl.2025.130214

Keke Yao , Yaxin Li , Wei Wei , Sisi Liu , Xiaoli Wang , Jiamin Xu , Ranran Zhang , Zhigang Wu , Chunyan Guo , Leifu Yang , Liming Hu

{"title":"Synthesis and biological evaluation of novel 4-Arylaminoquinolines derivatives as EGFR/HDAC inhibitors","authors":"Keke Yao , Yaxin Li , Wei Wei , Sisi Liu , Xiaoli Wang , Jiamin Xu , Ranran Zhang , Zhigang Wu , Chunyan Guo , Leifu Yang , Liming Hu","doi":"10.1016/j.bmcl.2025.130214","DOIUrl":"10.1016/j.bmcl.2025.130214","url":null,"abstract":"<div><div>Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the role of epigenetic modifications, such as histone deacetylation, in cancer progression underscore the need for novel therapeutic strategies. This study reports the design, synthesis, and biological evaluation of novel 4-arylaminoquinoline derivatives as dual inhibitors targeting EGFR and histone deacetylase (HDAC). Leveraging structure-activity relationship insights, a series of compounds were synthesized by integrating pharmacophoric elements of EGFR-TKIs and HDAC inhibitors and their kinase and cellular activities were evaluated. Compound <strong>22c2</strong> exhibited the highest inhibitory activities against EGFR (IC<sub>50</sub> = 4.81 nM) and HDAC (IC<sub>50</sub> = 119.4 nM and 354.8 nM for HDAC1 and HDAC3, respectively). Moreover, <strong>22c2</strong> demonstrated excellent anti-proliferative effects on four human cancer cell lines. These findings provide a foundation for developing dual EGFR/HDAC inhibitors as potential anticancer therapeutics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130214"},"PeriodicalIF":2.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747689","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

A small-molecule pretargeting approach for PSMA-targeted conjugates psma靶向偶联物的小分子预靶向方法。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-28 DOI: 10.1016/j.bmcl.2025.130213

Nooshin Mesbahi, Hosog Yoon, Melody D. Fulton, Clifford E. Berkman

引用次数: 0

Discovery of 4-((quinolin-8-ylthio)methyl)benzamide derivatives as a new class of SARS-CoV-2 nsp13 inhibitors 发现4-（（喹啉-8-基硫代）甲基）苯甲酰胺衍生物作为一类新的SARS-CoV-2 nsp13抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-25 DOI: 10.1016/j.bmcl.2025.130207

Danchen Fan , Yuanting Huang , Rui Yao , Guo Zhang , Shengyong Yang , Linli Li

引用次数: 0

Redox-responsive ferulic acid-biotin conjugate: Design, synthesis, and enhanced anticancer efficacy 氧化还原反应阿魏酸-生物素缀合物：设计、合成和增强抗癌功效

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-25 DOI: 10.1016/j.bmcl.2025.130209

Xiaoshuang Dai , Ke Mei , Jianpeng Liu , Bin Sun , Neng Qiu

{"title":"Redox-responsive ferulic acid-biotin conjugate: Design, synthesis, and enhanced anticancer efficacy","authors":"Xiaoshuang Dai , Ke Mei , Jianpeng Liu , Bin Sun , Neng Qiu","doi":"10.1016/j.bmcl.2025.130209","DOIUrl":"10.1016/j.bmcl.2025.130209","url":null,"abstract":"<div><div>In this study, ferulic acid (FA) was conjugated with biotin via a disulfide bond to improve its anticancer activity. The resulting conjugate (FA-SS-Bio) was characterized by proton nuclear magnetic resonance (<sup>1</sup>H NMR) and exhibited an amorphous structure, in contrast to the crystalline nature of FA. FA-SS-Bio demonstrated accelerated drug release under reductive and oxidative conditions. Biotinylation significantly increased cell uptake of the drug in biotin receptor (BR)-positive HeLa and MCF-7 cells, as confirmed by cellular uptake studies and molecular docking, which revealed strong biotin-BR interactions. Additionally, the cytotoxicity of FA-SS-Bio was significantly improved, with IC<sub>50</sub> values that were 2.94-fold and 2.95-fold lower than those of free FA against HeLa and MCF-7 cells, respectively. BR blockade with biotin reduced FA-SS-Bio cytotoxicity in a concentration-dependent manner, confirming biotin-mediated targeting. Apoptosis assays showed enhanced FA-induced apoptosis due to biotin and disulfide bonds. FA-SS-Bio demonstrated excellent blood compatibility, with a hemolysis rate below 0.5 %, compared to ∼1.5 % for FA. Additionally, FA-SS-Bio exhibited higher cell viability in MCF-10 A cells than in cancer cells, highlighting its favorable safety profile. These findings provide a novel perspective on the design of prodrug conjugates for improved cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130209"},"PeriodicalIF":2.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715530","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

PEG-ASO conjugates for efficient targeted delivery and migration inhibition in Cancer cell PEG-ASO偶联物在肿瘤细胞中的有效靶向递送和迁移抑制

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130208

Chunhui Zhao , Xiangjun Li , Zixin He , Chun Ye , Feng Chen , Jia Cheng

引用次数: 0

Design, synthesis, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors 新型苯丙氨酸衍生物蘑菇酪氨酸酶抑制剂的设计、合成、分子对接和ADME

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130211

Longhao Wang, Shunshun Lei, Liyun Du, Chengyao Lai, Weijie Yang, Liqin Qiu, Rihui Cao

{"title":"Design, synthesis, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors","authors":"Longhao Wang, Shunshun Lei, Liyun Du, Chengyao Lai, Weijie Yang, Liqin Qiu, Rihui Cao","doi":"10.1016/j.bmcl.2025.130211","DOIUrl":"10.1016/j.bmcl.2025.130211","url":null,"abstract":"<div><div>Tyrosinase is the key rate-limiting enzyme for melanin synthesis. The accumulation and excessive production of melanin lead to skin pigmentation. Therefore, tyrosinase is the target of tyrosinase inhibitors to control melanin synthesis. Only a few TYR inhibitors have been proven to be effective and safe to treat skin pigmentation. This highlights the importance of developing new tyrosinase inhibitors. Based on the reported tyrosinase inhibitors with phenylalanine structure, a series of novel phenylalanine derivatives were synthesized and investigated as mTYR inhibitors. The results demonstrated that most of these derivatives had more potent mTYR inhibitory activities than positive controls. Compound <strong>3e</strong> was found to be the strongest inhibitor with an IC<sub>50</sub> value of 4.86 ± 0.026 μM. The Lineweaver-Burk plots of mTYR inhibition kinetics revealed that the selected compounds <strong>2d</strong> and <strong>3e</strong> were reversible and competitive inhibitors. In addition, molecular docking results of compounds <strong>2d</strong> and <strong>3e</strong> show they could compete with the substrate for the active center, including mTYR and hTYR. And the ADME prediction of selected derivatives assess the potential druglikeness. These results indicated that this class of compounds could be used as leads for developing new TYR inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130211"},"PeriodicalIF":2.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725539","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