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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 Q1 CHEMISTRY, MEDICINAL 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

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. D1 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 NecroX-7 and Eriodictyol-7-O-glucoside 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.

铁蛋白沉积是治疗损伤相关疾病的一个很有前景的靶点,然而铁蛋白沉积抑制剂的多样性仍然有限。在本研究中,最初的结构优化促使我们关注 N-H 键的键解离焓(BDE)和自由基清除剂在磷脂双分子层中的驻留时间,这可能在铁突变抑制效力中发挥重要作用。因此,我们发现了化合物 D1,它具有强效的铁突变抑制作用、高自由基清除能力和适度的膜渗透性。在氧糖剥夺/再氧合(OGD/R)模型中,D1 表现出明显的神经保护作用;在体内中风模型中,D1 经静脉注射治疗后可减少梗死体积。基于这一策略的进一步筛选发现,NecroX-7 和 Eriodictyol-7-O-glucoside 是具有高极性结构特征的新型铁突变抑制剂。这种方法弥合了自由基清除剂和铁蛋白沉积抑制剂之间的差距,为新型铁蛋白沉积抑制剂的开发提供了研究基础和见解。
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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 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-07-12 DOI: 10.1021/acs.jmedchem.4c00878
Fuhao Jiang, Min Yu, Yuru Liang, Kuiling Ding, Yang Wang
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 21b, featuring a 3H-imidazo[4,5-b]pyridine core, displayed excellent targeting capabilities on katanin and tubulin, along with notable antiproliferative and antimetastatic effects. Mechanistic studies revealed that 21b disrupts the microtubule network in tumor cells, leading to G2/M cell cycle arrest and apoptosis induction. Importantly, 21b 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 21b presents a novel mechanism for disrupting microtubule dynamics, warranting further investigation as a dual-targeted antitumor agent with potential antimultidrug resistance properties.
破坏微管动力学已成为一种很有前景的癌症治疗策略。然而,耐药性仍然是阻碍微管靶向药物开发的一个挑战。在这项工作中,我们设计、合成并评估了一类新型二芳基取代的融合杂环,证明它们是有效的卡他宁和微管蛋白双重调节剂,具有抗肿瘤活性。经过三轮逐步优化,以 3H-咪唑并[4,5-b]吡啶为核心的化合物 21b 显示出对卡他宁和小管蛋白的卓越靶向能力,以及显著的抗增殖和抗转移作用。机理研究表明,21b 能破坏肿瘤细胞中的微管网络,导致 G2/M 细胞周期停滞并诱导细胞凋亡。重要的是,21b 能显著抑制 MDA-MB-231 和 A549/T 异种移植肿瘤模型中的肿瘤生长,且无明显毒性和副作用。总之,化合物 21b 提出了一种破坏微管动力学的新机制,作为一种具有潜在抗多药耐药性的双靶向抗肿瘤药物,值得进一步研究。
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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 Q1 CHEMISTRY, MEDICINAL 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

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 NO2). 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.

本视角是我们对美国 FDA 批准的含氮杂环小分子药物(1938-2012 年)分析的延续。在本研究中,我们报告了 2013 年 1 月至 2023 年 12 月期间批准的 321 种独特的新小分子药物的药物结构和性质分析,以及硫、氟等重要杂原子和关键小氮取代基(CN 和 NO2)的频率信息。最显著的变化是含有至少一个氮杂环的药物数量大幅增加--82%,而此前几十年的这一比例仅为 59%,同时每种药物中氮杂环的数量也大幅增加。吡啶从哌啶(第 2 位)手中夺走了氮杂环出现频率第一的宝座,嘧啶(第 5 位)、吡唑(第 6 位)和吗啉(第 9 位)则是前 10 位中的佼佼者。值得注意的是,融合氮杂环的数量也很高,这显然主要是受新批准的抗癌药物的推动。
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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 Q1 CHEMISTRY, MEDICINAL 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
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 d-glucose or a C5-epimer (i.e., l-idose or l-iduronic acid) conjugated with various lipophilic groups was synthesized and investigated for antiviral activity. Sulfated higher oligosaccharides of d-glucose or l-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 l-iduronic acid congeners. Lipophilic groups such as cholestanol and C18-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.
在此,我们报告了一系列新型肝素两亲化合物的合成和生物学评价,它们可作为肝素酶和 SARS-CoV-2 的抑制剂。通过采用量身定制的合成策略,我们合成了一个含有 d-葡萄糖或 C5-表聚体(即 l-idose 或 l-尿酸)并与各种亲脂基团共轭的高硫酸化同源寡糖库,并对其进行了抗病毒活性研究。具有亲脂性苷元的 d-葡萄糖或 l-依多糖硫酸化高寡糖显示出了与 pixatimod(PG545)相似或更强的抗 SARS-CoV-2 和抗肝癌活性,并且比它们的同源物 l-依多糖酸更强。胆甾醇和 C18 脂肪族取代物等亲脂基团比官能团附加亲脂分子更具优势。这些发现证实,对高寡糖、硫酸化程度和亲油基团进行微调,可以产生具有强效抗 SARS-CoV-2 活性的化合物。
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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 Q1 CHEMISTRY, MEDICINAL 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

Targeting Ca2+/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.

利用 RNAi 纳米技术靶向巨噬细胞中的 Ca2+/calmodulin 依赖性蛋白激酶 γ (CaMKIIγ)是诊断和治疗动脉粥样硬化的一种创新且前景广阔的策略。然而,由于目前将 siRNA 纳米颗粒(NP)系统性地输送到动脉粥样硬化斑块所面临的挑战以及动脉粥样硬化斑块的复杂性,这种方法仍然难以实现。在这里,我们展示了一种基于噻吩噻二唑的近红外-II(NIR-II)有机聚集诱导发射(AIE)平台的潜力,该平台封装了Camk2g siRNA,可有效靶向巨噬细胞中的CaMKIIγ,用于动脉粥样硬化的动态成像和图像引导基因治疗。纳米粒子有效降低了斑块巨噬细胞中 CaMKIIγ 的表达,增加了渗出受体 MerTK 的表达,从而减少了主动脉斑块模型中病变坏死核心区的面积。我们的治疗方法凸显了近红外II(NIR-II)AIEgens在动脉粥样硬化成像和图像引导治疗方面的巨大前景。
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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 Q1 CHEMISTRY, MEDICINAL 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

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 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.

发现有效而安全的抗肥胖药物仍然是一个充满挑战但又前景广阔的领域。我们之前的研究发现,布沙达汀衍生物是潜在的抗肥胖药物。然而,8a-甲醛分子使它们不适合药物开发。在本研究中,我们设计了两个系列的新型衍生物来改变这一结构特征。通过结构-活性关系研究,我们阐明了 8a-醛基在毒性诱导中的作用。我们发现了以 8a-N-acylhydrazone 分子为特征的化合物 14d,它具有显著的降血脂活性并能降低毒性。化合物 14d 与我们的先导化合物 3 具有相似的降血脂机理,但药代动力学特性和安全性得到了改善。口服和注射 14d 均可显著降低饮食诱导肥胖小鼠的体重增加,改善代谢综合征。我们的研究结果表明,14d 是一种很有前景的抗肥胖药物,并强调了用 N-酰腙取代醛基来增强类似药物特性的潜力。
{"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 Q1 CHEMISTRY, MEDICINAL 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

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 A1AR in living cells. We pharmacologically demonstrate covalent labeling of A1AR expressed in living cells while the orthosteric binding site remains available. The probes were imaged using confocal microscopy and fluorescence correlation spectroscopy to study A1AR localization and dynamics in living cells. Additionally, the probes allowed visualization of the specific localization of A1ARs endogenously expressed in dorsal root ganglion (DRG) neurons. LD probes developed here hold promise for illuminating ligand-binding, receptor signaling, and trafficking of the A1AR in more physiologically relevant environments.

研究蛋白质在原生细胞环境中的功能和动态对基础科学的发展至关重要。为了克服对蛋白质进行基因修饰的要求或可分离荧光配体的限制,配体定向(LD)化学最近已成为标记原生蛋白质的一种补充性生物对等方法。在这里,我们介绍了在活细胞中标记 A1AR 的第一种配体定向化学方法的合理设计、开发和应用。我们用药理学方法证明了在活细胞中表达的 A1AR 的共价标记,同时正交结合位点仍然可用。我们使用共聚焦显微镜和荧光相关光谱对探针进行了成像,以研究 A1AR 在活细胞中的定位和动态。此外,这些探针还能观察到背根神经节(DRG)神经元中内源性表达的 A1AR 的特异性定位。本文开发的LD探针有望在更多生理相关环境中揭示A1AR的配体结合、受体信号转导和迁移。
{"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 Q1 CHEMISTRY, MEDICINAL 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

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-n) for fluorescence imaging and surgical navigation of breast cancer through a drug repositioning strategy. Notably, YQGN-7, with its high cellular affinity (Kd 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.

乳腺癌是全球女性最常见的癌症,给治疗带来了巨大挑战。保乳手术(BCS)是根治性乳房切除术的一种创伤和痛苦较小的替代方法,它不仅能保留乳房的外观,还有助于术后功能的恢复。然而,准确识别肿瘤、精确划分边缘和彻底切除转移灶仍然是复杂的手术挑战,而目前成像技术的局限性(包括肿瘤摄取率低和信号对比度低)加剧了这一挑战。为了应对这些挑战,我们的研究开发了一系列 GnRHR 靶向探针(YQGN-n),通过药物重新定位策略进行乳腺癌的荧光成像和手术导航。值得注意的是,YQGN-7 具有很高的细胞亲和力(Kd 为 217.8 nM),对乳腺癌肿瘤具有卓越的选择性和特异性,在肿瘤摄取和药代动力学特性方面超越了 ICG 等传统成像剂。此外,YQGN-7 在原发性乳腺肿瘤和转移瘤的手术导航方面也很有效,这凸显了它作为乳腺放射治疗领域革命性工具的潜力。
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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 Q1 CHEMISTRY, MEDICINAL 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

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 (EC50 = 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 R-7d as a potent human TLR2 activator. It demonstrated subnanomolar activity (EC50 = 116 pM) in human THP-1 cells, comparable to that of diprovocim (EC50 = 110 pM). Experiments revealed that R-7d enhances NF-kB promoter activation through TLR2/TLR1 heterodimers rather than TLR2/TLR6. The discovery of R-7d as a robust human TLR2 agonist opens up new possibilities for combination therapies.

Toll 样受体 2 (TLR2) 在检测微生物病原体相关分子模式方面起着至关重要的作用,具有作为疫苗和抗肿瘤疗法佐剂的潜在应用价值。在这里,我们介绍了 CaLGL-1 及其衍生物的克级合成方法,这些天然产物可激活小鼠 TLR2(EC50 = 3.2 μM)。该合成涉及一个简化的六步反应序列,利用氧化剂促进的缩醛化反应,有效地保留了对酸敏感的糖苷键,从而保持了化合物的功能完整性。我们的结构-活性关系研究发现,R-7d 是一种强效的人类 TLR2 激活剂。它在人 THP-1 细胞中表现出亚纳摩尔活性(EC50 = 116 pM),与二溴氯丙烷(EC50 = 110 pM)相当。实验表明,R-7d 可通过 TLR2/TLR1 异二聚体而不是 TLR2/TLR6 增强 NF-kB 启动子的激活。R-7d 是一种强效的人类 TLR2 激动剂,它的发现为联合疗法开辟了新的可能性。
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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 Q1 CHEMISTRY, MEDICINAL 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

The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin 13 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 13, 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 13 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.

探索基于天然环肽的新型抗癌化合物已成为当代大环药物研究进展中的一个重要范例。Phakellistatin 13 是一种从棕色海绵中提取的环七肽,具有显著的抗肿瘤活性。在这项研究中,我们设计并合成了一系列手性环肽,在天然环肽 Phakellistatin 13 的不同部位加入了刚性异吲哚啉酮分子,旨在研究构象受限环肽作为潜在抗肿瘤药物的可能性。由交替的 l-/d- 氨基酸残基组成的环肽 3 具有良好的抗肝细胞癌效果。详细的生物学实验表明,Phakellistatin 13 类似物能有效抑制肿瘤细胞的增殖,诱导细胞凋亡和自噬,同时还能通过调节 p53 和丝裂原活化蛋白激酶(MAPK)信号通路导致细胞周期停滞。这项研究不仅为化学结构修饰提供了有价值的见解,而且有助于深入了解天然环肽类药物开发的生物学机制。
{"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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Journal of Medicinal Chemistry
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