Bioorganic & Medicinal Chemistry Letters最新文献_第7页

Synthesis of K+ channel radioligand [18F]5-methyl-3-fluoro-4-aminopyridine and PET imaging in mice K+ 通道放射性配体[18F]5-甲基-3-氟-4-氨基吡啶的合成和小鼠 PET 成像。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.129991

Yang Sun, Karla M. Ramos-Torres, Kazue Takahashi, Amal Tiss, Lauren L. Zhang, Pedro Brugarolas

{"title":"Synthesis of K+ channel radioligand [18F]5-methyl-3-fluoro-4-aminopyridine and PET imaging in mice","authors":"Yang Sun, Karla M. Ramos-Torres, Kazue Takahashi, Amal Tiss, Lauren L. Zhang, Pedro Brugarolas","doi":"10.1016/j.bmcl.2024.129991","DOIUrl":"10.1016/j.bmcl.2024.129991","url":null,"abstract":"<div><div>[<sup>18</sup>F]3-fluoro-4-aminopyridine ([<sup>18</sup>F]3F4AP) is the first positron emission tomography (PET) radioligand that targets voltage-gated potassium (K<sup>+</sup>) channels in the brain for imaging demyelination. [<sup>18</sup>F]3F4AP exhibits high brain penetration, favorable kinetics for PET imaging, and high sensitivity to demyelinating lesions. However, recent studies in awake human subjects indicate lower metabolic stability than in anesthetized animals, resulting in reduced brain uptake. Therefore, there is a need for novel radioligands for K<sup>+</sup> channels with suitable pharmacological properties and enhanced metabolic stability. Recent <em>in vitro</em> studies demonstrate that 5-methyl-3-fluoro-4-aminopyridine (5Me3F4AP) exhibits comparable binding affinity to K<sup>+</sup> channels, pK<sub>a</sub>, logD, and membrane permeability as 3F4AP, and a slower enzymatic metabolic rate, suggesting its potential as a K<sup>+</sup> channel PET tracer. In this study, we describe the radiochemical synthesis of [<sup>18</sup>F]5Me3F4AP using an isotope exchange method from the corresponding 3-fluoro-5-methyl-4-nitropyridine <em>N</em>-oxide, followed by a palladium on carbon mediated hydrogenation of the nitro and <em>N</em>-oxide groups. This method yielded [<sup>18</sup>F]5Me3F4AP with high purity and acceptable molar activity. PET/CT studies using naïve mice demonstrate that [<sup>18</sup>F]5Me3F4AP effectively crosses the blood–brain barrier and has comparable kinetics to [<sup>18</sup>F]3F4AP. These findings strongly suggest that [<sup>18</sup>F]5Me3F4AP is a promising candidate for neuroimaging applications and warrant further studies to investigate its sensitivity to lesions and <em>in vivo</em> metabolic stability.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129991"},"PeriodicalIF":2.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454436","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

Synchrotron Radiation: A Key Tool for Drug Discovery 同步辐射：药物发现的关键工具。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-13 DOI: 10.1016/j.bmcl.2024.129990

Fengcheng Li , Runze Liu , Wenjun Li , Mingyuan Xie , Song Qin

{"title":"Synchrotron Radiation: A Key Tool for Drug Discovery","authors":"Fengcheng Li , Runze Liu , Wenjun Li , Mingyuan Xie , Song Qin","doi":"10.1016/j.bmcl.2024.129990","DOIUrl":"10.1016/j.bmcl.2024.129990","url":null,"abstract":"<div><div>Synchrotron radiation is extensively utilized in the domains of materials science, physical chemistry, and life science, resulting from its high intensity, exceptional monochromaticity, superior collimation, and broad wave spectrum. This top-notch light source has also made significant contributions to the progress of biomedicine. The advancement of synchrotron radiation-based X-ray and protein crystallography technologies has created new prospects for drug discovery. These innovative techniques have opened up exciting avenues in the field. The investigation of protein crystal structures and the elucidation of the spatial configuration of biological macromolecules have revealed intricate details regarding the modes of protein binding. Furthermore, the screening of crystal polymorphs and ligands has laid the groundwork for rational drug modification and the improvement of drug physicochemical properties. As science and technology continue to advance, the techniques for analyzing structures using synchrotron radiation sources and the design of corresponding crystallographic beamline stations are undergoing continuous enhancement. These cutting-edge tools and facilities are expected to expedite the drug development process and rectify the current situation of a lack of targeted drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129990"},"PeriodicalIF":2.5,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454435","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 sulfone containing metallo-β-lactamase inhibitors with reduced bacterial cell efflux and histamine release issues 发现含砜金属-β-内酰胺酶抑制剂，可减少细菌细胞外流和组胺释放问题。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-11 DOI: 10.1016/j.bmcl.2024.129989

Frank Bennett , Yuhua Huang , Shuzhi Dong , Jinlong Jiang , David Hunter , Zhiqiang Zhao , Xin Gu , Jack D. Scott , Haiqun Tang , Dexi Yang , Li Xiao , Giovanna Scapin , Thierry Fischmann , Asra Mirza , Priya Dayananth , Ronald E. Painter , Artjohn Villafania , Charles G. Garlisi , Rumin Zhang , Todd W. Mayhood , Alexander Pasternak

引用次数: 0

Diffusion of 1O2 along the PNA backbone diminishes the efficiency of photooxidation of PNA/DNA duplexes by biphenyl photosensitizer 1O2 沿 PNA 主干扩散会降低联苯光敏剂对 PNA/DNA 双链体的光氧化效率。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-11 DOI: 10.1016/j.bmcl.2024.129988

Yaoyao Du, Takashi Kanamori, Yuma Yaginuma, Nanai Yoshida, Shota Kaneko, Hideya Yuasa

{"title":"Diffusion of 1O2 along the PNA backbone diminishes the efficiency of photooxidation of PNA/DNA duplexes by biphenyl photosensitizer","authors":"Yaoyao Du, Takashi Kanamori, Yuma Yaginuma, Nanai Yoshida, Shota Kaneko, Hideya Yuasa","doi":"10.1016/j.bmcl.2024.129988","DOIUrl":"10.1016/j.bmcl.2024.129988","url":null,"abstract":"<div><div>Nitrobiphenyl photosensitizer (NBP)-peptide nucleic acids (PNA) conjugates were synthesized to develop a tool for photo-knockdown of target DNAs. The presence of NBP hardly hindered duplex formation with the complementary single strand DNA as demonstrated by the comparison of <em>T</em><sub>m</sub> values and CD spectra with those for standard PNA/DNA duplexes. However, the photooxidation of guanines in NBP-PNA/DNAs was significantly less effective than those of corresponding NBP-DNA/DNA. Production of singlet oxygen (<sup>1</sup>O<sub>2</sub>) during the photooxidation was confirmed by consumption of furfuryl alcohol, a <sup>1</sup>O<sub>2</sub> detector. The poor photooxidation efficiency was ameliorated with <sup>1</sup>O<sub>2</sub> generated from an externally added NBP derivative. It was found that, when complexed with the sticky end of a double strand DNA, NBP-PNA was able to photooxidize G in the DNA/DNA duplex region, whereas G in the PNA/DNA duplex region was considerably unreactive. These results suggest that <sup>1</sup>O<sub>2</sub> produced from NBP-PNA tends to quench during diffusion along the PNA/DNA backbone, whereas quenching is less likely during diffusion along DNA/DNA region.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129988"},"PeriodicalIF":2.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454401","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

Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors 作为 NLRP3 炎症小体抑制剂的磺酰脲衍生物的设计、合成和生物学评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-10 DOI: 10.1016/j.bmcl.2024.129987

Haonan Feng , Donglai Li , Fuli Zhu , Caihong Jiang , Mengjun Su , Yichao Kong , Yonghao Zheng , Yaxia Yuan , Weiwei Huang , Xiabin Chen , Lei Ma

{"title":"Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors","authors":"Haonan Feng , Donglai Li , Fuli Zhu , Caihong Jiang , Mengjun Su , Yichao Kong , Yonghao Zheng , Yaxia Yuan , Weiwei Huang , Xiabin Chen , Lei Ma","doi":"10.1016/j.bmcl.2024.129987","DOIUrl":"10.1016/j.bmcl.2024.129987","url":null,"abstract":"<div><div>The NLRP3 inflammasome has been extensively studied in recent years and its aberrant activation can exacerbate inflammatory responses, contributing to various diseases. MCC950, a sulfonylurea drug, is a potent selective inhibitor of the NLRP3 inflammasome. However, its clinical development was halted due to hepatotoxicity, and studies have indicated significant reduction in activity among its metabolites. Building upon MCC950, we referenced substitution sites of NP3-146 for structural modifications aimed at addressing potential metabolism-related issues. Consequently, we synthesized a series of sulfonylurea derivatives. Ultimately, the optimized compound <strong>C4</strong> exhibited a remarkable 80.39 % inhibition of IL-1<em>β</em> at 2 μM, with an IC<sub>50</sub> value of 0.805 μM. In conclusion, compound <strong>C4</strong> shows potential as a lead compound and warrants further development as an anti-inflammatory NLRP3 inhibitor.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129987"},"PeriodicalIF":2.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454384","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

Design and optimization of novel Tetrahydro-β-carboline-based HDAC inhibitors with potent activities against tumor cell growth and metastasis 设计和优化新型四氢-β-咔啉基 HDAC 抑制剂，使其具有抑制肿瘤细胞生长和转移的强效活性

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-10 DOI: 10.1016/j.bmcl.2024.129986

Shule Fan , Zeyi Wan , Yuhua Qu , Wenxia Lu, Xiangzhi Li, Feifei Yang, Hua Zhang

引用次数: 0

Identification of 3-methyl-1-(3-methylpyridin-2-yl)-1H-pyrazol-5-ol as promising neuroprotective agent 鉴定 3-甲基-1-（3-甲基吡啶-2-基）-1H-吡唑-5-醇为有前途的神经保护剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-10 DOI: 10.1016/j.bmcl.2024.129983

Peng Zhu , Yulu Wu , Zhikang Du , Siyi Li , Jiaming Li , Xin Lu , Xueyang Jiang

{"title":"Identification of 3-methyl-1-(3-methylpyridin-2-yl)-1H-pyrazol-5-ol as promising neuroprotective agent","authors":"Peng Zhu , Yulu Wu , Zhikang Du , Siyi Li , Jiaming Li , Xin Lu , Xueyang Jiang","doi":"10.1016/j.bmcl.2024.129983","DOIUrl":"10.1016/j.bmcl.2024.129983","url":null,"abstract":"<div><div>Pyrazolol derivatives are gaining significant attention for their diverse pharmacological effects, such as analgesic, anti-inflammatory, antioxidant, and anticancer activities. In this study, 20 pyrazolol derivatives were designed and synthesized to develop an anti-ischemic stroke formulation with free radical scavenging activity. Most of these synthesized compounds demonstrated antioxidant capabilities in DPPH, ABTS radical scavenging, and ORAC<sub>FL</sub> assays. The methyl-substituted compound <strong>Y12</strong>, in particular, showed exceptional antioxidant capacity. Additionally, these compounds showed excellent neurocytoprotective effects in the SH-SY5Y cell injury model subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Notably, <strong>Y12</strong> exhibited significant metal chelating activity with Cu<sup>2+</sup>. In vivo studies confirmed that compound <strong>Y12</strong> has neuroprotective effects and can significantly reduce the infarct area in a mouse model of focal cerebral ischemia induced by transient middle cerebral artery occlusion (tMCAO).</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129983"},"PeriodicalIF":2.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454434","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

The heterodimer of 2-amino-1,8-naphthyridine and 3-aminoisoquinoline binds to the CTG/CTG triad via hydrogen bonding 2-氨基-1,8-萘啶和 3-氨基异喹啉的异二聚体通过氢键与 CTG/CTG 三元组结合。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-10 DOI: 10.1016/j.bmcl.2024.129985

Shuhei Sakurabayashi, Takeshi Yamada, Kazuhiko Nakatani

引用次数: 0

Synthesis, optimization and antitumor activity evaluation of sulfonyl benzoyl hydrazide derivatives as novel human LSD1 inhibitors 磺酰基苯甲酰肼衍生物作为新型人类 LSD1 抑制剂的合成、优化和抗肿瘤活性评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-09 DOI: 10.1016/j.bmcl.2024.129982

Wei Ai , Zeping Zuo

引用次数: 0

Design, synthesis and biological evaluation of novel benzocoumarin derivatives as potent inhibitors of MAO-B activity 新型苯并香豆素衍生物作为 MAO-B 活性强效抑制剂的设计、合成和生物学评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-09 DOI: 10.1016/j.bmcl.2024.129984

Furkan Meletli , Cihan Gündüz , Mustafa Muhlis Alparslan , Azade Attar , Serap Demir , Ece İskit , Özkan Danış

引用次数: 0