Journal of Medicinal Chemistry最新文献

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Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers. 发现新的苯基四唑衍生物作为治疗缺血性中风的铁氧化酶抑制剂:从自由基清除剂发展而来的范例。
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c00211
Yang Lu, Zexu Shen, Yaping Xu, Haoran Lin, Liteng Shen, Yizhen Jin, Yu Guo, Jialiang Lu, Linjie Li, Yuxin Zhuang, Yuheng Jin, Weihao Zhuang, Wenhai Huang, Xiaowu Dong, Haibin Dai, Jinxin Che
{"title":"Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers.","authors":"Yang Lu, Zexu Shen, Yaping Xu, Haoran Lin, Liteng Shen, Yizhen Jin, Yu Guo, Jialiang Lu, Linjie Li, Yuxin Zhuang, Yuheng Jin, Weihao Zhuang, Wenhai Huang, Xiaowu Dong, Haibin Dai, Jinxin Che","doi":"10.1021/acs.jmedchem.4c00211","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00211","url":null,"abstract":"<p><p>Ferroptosis is a promising therapeutic target for injury-related diseases, yet diversity in ferroptosis inhibitors remains limited. In this study, initial structure optimization led us to focus on the bond dissociation enthalpy (BDE) of the N-H bond and the residency time of radical scavengers in a phospholipid bilayer, which may play an important role in ferroptosis inhibition potency. This led to the discovery of compound D1, exhibiting potent ferroptosis inhibition, high radical scavenging, and moderate membrane permeability. <b>D1</b> demonstrated significant neuroprotection in an oxygen glucose deprivation/reoxygenation (OGD/R) model and reduced infarct volume in an in vivo stroke model upon intravenous treatment. Further screening based on this strategy identified <b>NecroX-7</b> and <b>Eriodictyol-7-O-glucoside</b> as novel ferroptosis inhibitors with highly polar structural characteristics. This approach bridges the gap between free radical scavengers and ferroptosis inhibitors, providing a foundation for research and insights into novel ferroptosis inhibitor development.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Diaryl-Substituted Fused Heterocycles Targeting Katanin and Tubulin with Potent Antitumor and Antimultidrug Resistance Efficacy 发现以 Katanin 和 Tubulin 为靶标、具有强效抗肿瘤和抗多药耐药性的新型二芳基取代融合杂环化合物
IF 7.3 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c00878
Fuhao Jiang, Min Yu, Yuru Liang, Kuiling Ding, Yang Wang
{"title":"Discovery of Novel Diaryl-Substituted Fused Heterocycles Targeting Katanin and Tubulin with Potent Antitumor and Antimultidrug Resistance Efficacy","authors":"Fuhao Jiang, Min Yu, Yuru Liang, Kuiling Ding, Yang Wang","doi":"10.1021/acs.jmedchem.4c00878","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00878","url":null,"abstract":"Disrupting microtubule dynamics has emerged as a promising strategy for cancer treatment. However, drug resistance remains a challenge hindering the development of microtubule-targeting agents. In this work, a novel class of diaryl substituted fused heterocycles were designed, synthesized, and evaluated, which were demonstrated as effective dual katanin and tubulin regulators with antitumor activity. Following three rounds of stepwise optimization, compound <b>21b</b>, featuring a 3<i>H</i>-imidazo[4,5-<i>b</i>]pyridine core, displayed excellent targeting capabilities on katanin and tubulin, along with notable antiproliferative and antimetastatic effects. Mechanistic studies revealed that <b>21b</b> disrupts the microtubule network in tumor cells, leading to G2/M cell cycle arrest and apoptosis induction. Importantly, <b>21b</b> exhibited significant inhibition of tumor growth in MDA-MB-231 and A549/T xenograft tumor models without evident toxicity and side effects. In conclusion, compound <b>21b</b> presents a novel mechanism for disrupting microtubule dynamics, warranting further investigation as a dual-targeted antitumor agent with potential antimultidrug resistance properties.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023). 美国 FDA 批准药物的氮杂环组成和特性更新(2013-2023 年)》。
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c01122
Christopher M Marshall, John G Federice, Chloe N Bell, Philip B Cox, Jon T Njardarson
{"title":"An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023).","authors":"Christopher M Marshall, John G Federice, Chloe N Bell, Philip B Cox, Jon T Njardarson","doi":"10.1021/acs.jmedchem.4c01122","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01122","url":null,"abstract":"<p><p>This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles. In this study we report drug structure and property analyses of 321 unique new small-molecule drugs approved from January 2013 to December 2023 as well as information about frequency of important heteroatoms such as sulfur and fluorine and key small nitrogen substituents (CN and NO<sub>2</sub>). The most notable change is an incredible increase in drugs containing at least one nitrogen heterocycle─82%, compared to 59% from preceding decades─as well as a significant increase in the number of nitrogen heterocycles per drug. Pyridine has claimed the #1 high-frequency nitrogen heterocycle occurrence spot from piperidine (#2), with pyrimidine (#5), pyrazole (#6), and morpholine (#9) being the big top 10 climbers. Also notable is high number of fused nitrogen heterocycles, apparently driven largely by newly approved cancer drugs.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2 作为强效抗病毒药物的两性肝素类抗 SARS-CoV-2
IF 7.3 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c00487
Mohit Chhabra, Chethan D. Shanthamurthy, Nanjudaswamy Vijendra Kumar, Sandhya Mardhekar, Sharath S. Vishweshwara, Norbert Wimmer, Naphak Modhiran, Daniel Watterson, Alberto A. Amarilla, Jonathan S. Cha, James R. Beckett, James J. De Voss, Yasmin Kayal, Israel Vlodavsky, Lauren R. Dorsett, Raymond A. A. Smith, Neha S. Gandhi, Raghavendra Kikkeri, Vito Ferro
{"title":"Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2","authors":"Mohit Chhabra, Chethan D. Shanthamurthy, Nanjudaswamy Vijendra Kumar, Sandhya Mardhekar, Sharath S. Vishweshwara, Norbert Wimmer, Naphak Modhiran, Daniel Watterson, Alberto A. Amarilla, Jonathan S. Cha, James R. Beckett, James J. De Voss, Yasmin Kayal, Israel Vlodavsky, Lauren R. Dorsett, Raymond A. A. Smith, Neha S. Gandhi, Raghavendra Kikkeri, Vito Ferro","doi":"10.1021/acs.jmedchem.4c00487","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00487","url":null,"abstract":"Herein, we report the synthesis and biological evaluation of a novel series of heparinoid amphiphiles as inhibitors of heparanase and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library of highly sulfated homo-oligosaccharides bearing <span>d</span>-glucose or a C5-epimer (i.e., <span>l</span>-idose or <span>l</span>-iduronic acid) conjugated with various lipophilic groups was synthesized and investigated for antiviral activity. Sulfated higher oligosaccharides of <span>d</span>-glucose or <span>l</span>-idose with lipophilic aglycones displayed potent anti-SARS-CoV-2 and antiheparanse activity, similar to or better than pixatimod (PG545), and were more potent than their isosteric <span>l</span>-iduronic acid congeners. Lipophilic groups such as cholestanol and C<sub>18</sub>-aliphatic substitution are more advantageous than functional group appended lipophilic moieties. These findings confirm that fine-tuning of higher oligosaccharides, degree of sulfation, and lipophilic groups can yield compounds with potent anti-SARS-CoV-2 activity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Near-Infrared II Fluorescence Imaging and Image-Guided siRNA Therapy of Atherosclerosis. 动脉粥样硬化的近红外 II 荧光成像和图像引导 siRNA 治疗。
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c01208
Jialu Gao, Kai Yu, Qiusi Luo, Mingbo Deng, Xiaowen Hou, Wumei Wang, Xiaodong Zeng, Xiaoxing Xiong, Yong He, Xuechuan Hong, Yuling Xiao
{"title":"Near-Infrared II Fluorescence Imaging and Image-Guided siRNA Therapy of Atherosclerosis.","authors":"Jialu Gao, Kai Yu, Qiusi Luo, Mingbo Deng, Xiaowen Hou, Wumei Wang, Xiaodong Zeng, Xiaoxing Xiong, Yong He, Xuechuan Hong, Yuling Xiao","doi":"10.1021/acs.jmedchem.4c01208","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01208","url":null,"abstract":"<p><p>Targeting Ca<sup>2+</sup>/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Development of Novel N-Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group. 通过探索醛基的药物特性,开发具有高抗肥活性和更高安全性的新型 N-酰腙衍生物
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c01242
Zhi Jiang, Yu-Tao Hu, Shi-Yao Guo, Yi-Xian Li, Dan-Dan Zhao, Li-Yuan Wei, Yu-Wei Lin, Shu-Min Xu, Shi-Liang Huang, Qingjiang Li, Jia-Heng Tan, Yong Rao, Shuo-Bin Chen, Zhi-Shu Huang
{"title":"Development of Novel <i>N</i>-Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group.","authors":"Zhi Jiang, Yu-Tao Hu, Shi-Yao Guo, Yi-Xian Li, Dan-Dan Zhao, Li-Yuan Wei, Yu-Wei Lin, Shu-Min Xu, Shi-Liang Huang, Qingjiang Li, Jia-Heng Tan, Yong Rao, Shuo-Bin Chen, Zhi-Shu Huang","doi":"10.1021/acs.jmedchem.4c01242","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01242","url":null,"abstract":"<p><p>The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound <b>14d</b>, featuring an 8a-<i>N</i>-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound <b>14d</b> shares a similar lipid-lowering mechanism with our lead compound <b>3</b>, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of <b>14d</b> significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify <b>14d</b> as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an <i>N</i>-acylhydrazone to enhance drug-like properties.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Ligand-Directed Labeling of the Adenosine A1 Receptor in Living Cells. 活细胞中腺苷 A1 受体的配体定向标记。
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c00835
Eleonora Comeo, Joëlle Goulding, Chia-Yang Lin, Marleen Groenen, Jeanette Woolard, Nicholas D Kindon, Clare R Harwood, Simon Platt, Stephen J Briddon, Laura E Kilpatrick, Peter J Scammells, Stephen J Hill, Barrie Kellam
{"title":"Ligand-Directed Labeling of the Adenosine A<sub>1</sub> Receptor in Living Cells.","authors":"Eleonora Comeo, Joëlle Goulding, Chia-Yang Lin, Marleen Groenen, Jeanette Woolard, Nicholas D Kindon, Clare R Harwood, Simon Platt, Stephen J Briddon, Laura E Kilpatrick, Peter J Scammells, Stephen J Hill, Barrie Kellam","doi":"10.1021/acs.jmedchem.4c00835","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00835","url":null,"abstract":"<p><p>The study of protein function and dynamics in their native cellular environment is essential for progressing fundamental science. To overcome the requirement of genetic modification of the protein or the limitations of dissociable fluorescent ligands, ligand-directed (LD) chemistry has most recently emerged as a complementary, bioorthogonal approach for labeling native proteins. Here, we describe the rational design, development, and application of the first ligand-directed chemistry approach for labeling the A<sub>1</sub>AR in living cells. We pharmacologically demonstrate covalent labeling of A<sub>1</sub>AR expressed in living cells while the orthosteric binding site remains available. The probes were imaged using confocal microscopy and fluorescence correlation spectroscopy to study A<sub>1</sub>AR localization and dynamics in living cells. Additionally, the probes allowed visualization of the specific localization of A<sub>1</sub>ARs endogenously expressed in dorsal root ganglion (DRG) neurons. LD probes developed here hold promise for illuminating ligand-binding, receptor signaling, and trafficking of the A<sub>1</sub>AR in more physiologically relevant environments.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Repurposing GnRH-A as a Near-Infrared Fluorescent Probe for Diagnosis and Surgical Navigation of Breast Cancer Tumors and Metastases. 将 GnRH-A 作为近红外荧光探针重新用于乳腺癌肿瘤和转移灶的诊断和手术导航。
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c01142
Haoran Xu, Zhuoyi Ye, Xin Gao, Yue Dai, Yang Luo, Zhihao Han, Yueqing Gu
{"title":"Repurposing GnRH-A as a Near-Infrared Fluorescent Probe for Diagnosis and Surgical Navigation of Breast Cancer Tumors and Metastases.","authors":"Haoran Xu, Zhuoyi Ye, Xin Gao, Yue Dai, Yang Luo, Zhihao Han, Yueqing Gu","doi":"10.1021/acs.jmedchem.4c01142","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01142","url":null,"abstract":"<p><p>Breast cancer, globally the most common cancer in women, presents significant challenges in treatment. Breast-conserving surgery (BCS), a less traumatic and painful alternative to radical mastectomy, not only preserves the breast's appearance but also supports postsurgical functional recovery. However, accurately identifying tumors, precisely delineating margins, and thoroughly removing metastases remain complex surgical challenges, exacerbated by the limitations of current imaging techniques, including poor tumor uptake and low signal contrast. Addressing these challenges, our study developed a series of GnRHR-targeted probes (YQGN-<i>n</i>) for fluorescence imaging and surgical navigation of breast cancer through a drug repositioning strategy. Notably, YQGN-7, with its high cellular affinity (<i>K</i><sub>d</sub> of 217.8 nM), demonstrates exceptional selectivity and specificity for breast cancer tumors, surpassing traditional imaging agents like ICG in tumor uptake and pharmacokinetic properties. Furthermore, YQGN-7's effectiveness in surgical navigation, both for primary breast tumors and metastases, highlights its potential as a revolutionary tool in BCS.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
The Development of a Highly Potent and Selective Human Toll-like Receptor 2 Agonist: Synthesis and Biological Evaluation of CaLGL-1 and Its Derivatives. 高效力和选择性人类 Toll 样受体 2 激动剂的开发:CaLGL-1 及其衍生物的合成与生物学评估。
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c00886
Hongbin Jia, Zhikuan Luo, Ruijun Jing, Bowen Yao, Tinghong Lv, Haixue Zheng, Xiaolei Wang
{"title":"The Development of a Highly Potent and Selective Human Toll-like Receptor 2 Agonist: Synthesis and Biological Evaluation of CaLGL-1 and Its Derivatives.","authors":"Hongbin Jia, Zhikuan Luo, Ruijun Jing, Bowen Yao, Tinghong Lv, Haixue Zheng, Xiaolei Wang","doi":"10.1021/acs.jmedchem.4c00886","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00886","url":null,"abstract":"<p><p>Toll-like receptor 2 (TLR2) plays a crucial role in detecting microbial pathogen-associated molecular patterns, offering potential applications as an adjuvant for vaccines and antitumor therapies. Here, we present the gram-scale synthesis of CaLGL-1 and its derivatives, natural products known for activating mouse TLR2 (EC<sub>50</sub> = 3.2 μM). This synthesis involves a streamlined six-step reaction sequence utilizing oxidant-promoted acetalization, effectively preserving the acid-sensitive glycosidic bond for maintaining the compounds' functional integrity. Our structure-activity relationship studies identified <b>R-7d</b> as a potent human TLR2 activator. It demonstrated subnanomolar activity (EC<sub>50</sub> = 116 pM) in human THP-1 cells, comparable to that of diprovocim (EC<sub>50</sub> = 110 pM). Experiments revealed that <b>R-7d</b> enhances NF-kB promoter activation through TLR2/TLR1 heterodimers rather than TLR2/TLR6. The discovery of <b>R-7d</b> as a robust human TLR2 agonist opens up new possibilities for combination therapies.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13. 探索天然大环肽 Phakellistatin 衍生的环肽抗肿瘤药物的潜力 13.
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-07-11 DOI: 10.1021/acs.jmedchem.4c00393
Tong Li, Shitian Jiang, Tingting Li, Hongyu Xu, Xiong Zhang, Rui Yan, Xiaodan Wu, Yingxue Jin, Zhiqiang Wang
{"title":"Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin <b>13</b>.","authors":"Tong Li, Shitian Jiang, Tingting Li, Hongyu Xu, Xiong Zhang, Rui Yan, Xiaodan Wu, Yingxue Jin, Zhiqiang Wang","doi":"10.1021/acs.jmedchem.4c00393","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00393","url":null,"abstract":"<p><p>The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin <b>13</b> is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin <b>13</b>, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin <b>13</b> analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
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