Bioorganic & Medicinal Chemistry最新文献_第9页

The application of PROTACs in immune-inflammation diseases PROTAC 在免疫炎症疾病中的应用

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-26 DOI: 10.1016/j.bmc.2024.117967

Chao Zhang , Xiuyun Sun , Peilu Song , Yu Rao

{"title":"The application of PROTACs in immune-inflammation diseases","authors":"Chao Zhang , Xiuyun Sun , Peilu Song , Yu Rao","doi":"10.1016/j.bmc.2024.117967","DOIUrl":"10.1016/j.bmc.2024.117967","url":null,"abstract":"<div><div>Immune-inflammatory diseases are a class of conditions with high prevalence that severely impact the quality of life. Current treatment strategies include immunosuppressants, glucocorticoids, and monoclonal antibodies. However, these approaches have certain limitations, such as poor membrane permeability, immunogenicity, and the requirement for injection in large molecule drugs. Small molecule compounds, on the other hand, suffer from issues like poor selectivity, inability to inhibit non-enzymatic functions, and biological compensation. These factors constrain the effectiveness of current therapeutic strategies in immune-inflammatory diseases. As a novel small molecule drug development technology, proteolysis-targeting chimeras (PROTACs) regulate protein levels by inducing interactions between target proteins and E3 ubiquitin ligases, leading to the selective degradation of target proteins. This technology has already shown promising therapeutic effects in the treatment of immune-inflammatory diseases. This review aims to comprehensively summarize the application of PROTAC technology in the field of immune inflammation and provide insights into its potential in treating immune-inflammatory diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117967"},"PeriodicalIF":3.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

310-Helix stabilization and screw sense control via stereochemically configured 4-atom hydrocarbon staples 通过立体化学配置的 4 原子碳氢化合物主链实现 310-Helix 稳定化和螺纹感应控制。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-22 DOI: 10.1016/j.bmc.2024.117963

Duc V.H. Tran, Ha T.N. Nguyen, Hee-Chul Ahn, Young-Woo Kim

{"title":"310-Helix stabilization and screw sense control via stereochemically configured 4-atom hydrocarbon staples","authors":"Duc V.H. Tran, Ha T.N. Nguyen, Hee-Chul Ahn, Young-Woo Kim","doi":"10.1016/j.bmc.2024.117963","DOIUrl":"10.1016/j.bmc.2024.117963","url":null,"abstract":"<div><div>The 3<sub>10</sub>-helix is a crucial secondary structure in proteins, playing an essential role in various protein–protein interactions, yet stabilizing it in biologically relevant peptides remains challenging. In this study, we investigated the potential of 4-atom hydrocarbon staples to stabilize 3<sub>10</sub>-helices in peptides. Using ring-closing metathesis, we demonstrated that the staple’s configuration is critical for both the stabilization and screw sense control of 3<sub>10</sub>-helices. Circular dichroism spectroscopy revealed that the <strong><em>R<sub>i</sub></em><sub>,</sub><em><sub>i</sub></em><sub>+3</sub><em>S</em>(4)</strong> staple—a 4-atom cross-link with (<em>R</em>)-configuration at the <em>i</em> position, (<em>S</em>)-configuration at the <em>i</em> + 3 position, and flanked by methyl groups—strongly induces right-handed 3<sub>10</sub>-helices, especially in sequences with proteinogenic <span>l</span>-amino acids. Furthermore, multiple staples effectively stabilized longer peptides, underscoring the versatility of this approach for applications in peptide therapeutics and biomolecular engineering.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117963"},"PeriodicalIF":3.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 critical analysis of design, binding pattern and SAR of benzo-fused heteronuclear compounds as VEGFR-2 inhibitors 对作为 VEGFR-2 抑制剂的苯并融合杂核化合物的设计、结合模式和 SAR 的重要分析。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-22 DOI: 10.1016/j.bmc.2024.117966

Mayank Kashyap, Saurabh Gupta, Yogita Bansal, Gulshan Bansal

{"title":"A critical analysis of design, binding pattern and SAR of benzo-fused heteronuclear compounds as VEGFR-2 inhibitors","authors":"Mayank Kashyap, Saurabh Gupta, Yogita Bansal, Gulshan Bansal","doi":"10.1016/j.bmc.2024.117966","DOIUrl":"10.1016/j.bmc.2024.117966","url":null,"abstract":"<div><div>Vascular endothelial growth factors (VEGFs) are a class of homodimeric ligands that bind to their receptors (VEGFRs) to carryout physiological and pathological angiogenesis essential for regulating homeostasis of body. Overexpression of VEGF results in metastasis of benign tumor into malignant tumor. An active role of VEGFR-2 in cancer angiogenesis makes it a major target for cancer therapy. FDA approved VEGFR-2 inhibitors like sorafenib, vemurafenib and dabrafenib, and monoclonal antibodies such as bevacizumab and ramucirumab are available in market but possess side effects like hypertension, CVS disorders, liver damage and adverse effects like Iatrogenicity. Several research groups across the globe have designed and reported varied small molecules from different heteronuclei like quinazoline, pyrimidine, coumarin, pyrazole, indoline, benzimidazole, benzoxazole, etc. as VEGFR-2 inhibitors based on the information available on active site of the receptor, and pharmacophoric features of FDA approved drugs. The present review compiles the information available on benzo-fused heteronuclear compounds including benzimidazole, benzoxazole and benzothiazole in recent years, with emphasis on their design, activity, structure–activity relationship (SAR) and docking analysis for understanding binding interactions in the active site of VEGFR-2. In addition to this, a topological similarity analysis of these compounds is performed taking sorafenib as template, and a comprehensive SAR is proposed for researchers to further explore the anticancer potential of these pharmacophore.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117966"},"PeriodicalIF":3.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Modulation of aryl hydrocarbon receptor activity by halogenated indoles 卤代吲哚对芳基烃受体活性的调节。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-19 DOI: 10.1016/j.bmc.2024.117964

Aneta Vrzalová , Radim Vrzal , Petr Nádvorník , Marek Šebela , Zdeněk Dvořák

{"title":"Modulation of aryl hydrocarbon receptor activity by halogenated indoles","authors":"Aneta Vrzalová , Radim Vrzal , Petr Nádvorník , Marek Šebela , Zdeněk Dvořák","doi":"10.1016/j.bmc.2024.117964","DOIUrl":"10.1016/j.bmc.2024.117964","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117964"},"PeriodicalIF":3.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 and evaluation of novel SHIP-1 inhibitors 发现和评估新型 SHIP-1 抑制剂。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-19 DOI: 10.1016/j.bmc.2024.117965

Jinmin Miao , Jianping Lin , Jiajun Dong , Ovini Amarasinghe , Emily R. Mason , Shaoyou Chu , Zihan Qu , Clayton C. Cullers , Karson S. Putt , Zhong-Yin Zhang

{"title":"Discovery and evaluation of novel SHIP-1 inhibitors","authors":"Jinmin Miao , Jianping Lin , Jiajun Dong , Ovini Amarasinghe , Emily R. Mason , Shaoyou Chu , Zihan Qu , Clayton C. Cullers , Karson S. Putt , Zhong-Yin Zhang","doi":"10.1016/j.bmc.2024.117965","DOIUrl":"10.1016/j.bmc.2024.117965","url":null,"abstract":"<div><div>Src Homology 2-containing Inositol 5′-Phosphatase-1 (SHIP-1), encoded by <em>INPP5D</em>, has been identified as an Alzheimer’s disease (AD) risk-associated gene through recent genetic and epigenetic studies. SHIP-1 confers AD risk by inhibiting the TREM2 cascade and reducing beneficial microglial cellular processes, including phagocytosis. While several small molecules have been reported to modulate SHIP-1 activity, their limited selectivity and efficacy in advanced models restricted their potential as therapeutic agents or probes for biological studies. Herein, we validated and implemented a high-throughput screening platform to explore new chemotypes that can modulate the phosphatase activity of SHIP-1. We screened 49,260 central nervous system (CNS)-penetrate compounds sourced from commercial vendors using the malachite green-based assay for anti-SHIP-1 activity. Through analysis, prioritization, and validation of the screening hits, we identified three novel types of scaffolds that inhibit the SHIP-1 phosphatase activity with IC<sub>50</sub>s as low as 46.6 µM. To improve the inhibitory activity of these promising hits, we carried out structure–activity relationship (SAR) studies, resulting in a lead molecule SP3-12 that inhibits SHIP-1 with an IC<sub>50</sub> value of 6.1 μM. Kinetic analyses of SP3-12 revealed that its inhibition mechanism is competitive, with a <em>K</em><sub>i</sub> value of 3.2 µM for SHIP-1 and a 7-fold selectivity over SHIP-2. Furthermore, results from testing in a microglial phagocytosis/cell health high content assay indicated that SP3-12 could effectively activate phagocytosis in human microglial clone 3 (HMC3) cells, with an EC<sub>50</sub> of 2.0 µM, without cytotoxicity in the dose range. Given its potency, selectivity, and cellular activity, SP3-12 emerges as a promising small molecule inhibitor with potential for investigating the biological functions of SHIP-1.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117965"},"PeriodicalIF":3.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Photodynamic therapy: An emerging therapeutic modality in dentistry 光动力疗法：一种新兴的牙科治疗模式。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-19 DOI: 10.1016/j.bmc.2024.117962

Nandita Suresh , Betsy Joseph , Pradeesh Sathyan , Vishnupriya K. Sweety , Tuomas Waltimo , Sukumaran Anil

{"title":"Photodynamic therapy: An emerging therapeutic modality in dentistry","authors":"Nandita Suresh , Betsy Joseph , Pradeesh Sathyan , Vishnupriya K. Sweety , Tuomas Waltimo , Sukumaran Anil","doi":"10.1016/j.bmc.2024.117962","DOIUrl":"10.1016/j.bmc.2024.117962","url":null,"abstract":"<div><div>Photodynamic Therapy (PDT) is a rapidly evolving, non-invasive treatment modality with considerable promise in dental pharmacotherapeutics. This review article comprehensively examines PDT, beginning with its principles and then delving into its diverse applications in dentistry, including periodontal disease, endodontics, oral cancer, dental implants, and dental caries. Each area presents the latest research and discusses the potential benefits and challenges. The unique advantages of PDT are highlighted, such as selective targeting, broad-spectrum antimicrobial effect, lack of resistance development, and its synergistic effect with other treatments. However, challenges such as photosensitizer delivery, light penetration, oxygen availability, and the need to standardize protocols are also acknowledged. The review further explores future perspectives of PDT in dentistry, including advancements in photosensitizer design, overcoming hypoxic limitations, personalized protocols, integration with other therapies, and standardization and regulation. The potential of advanced technologies, such as nanotechnology and synthetic biology, to improve PDT outcomes is also discussed. The review concludes that while PDT has shown immense potential to revolutionize dental pharmacotherapeutics, further high-quality research is needed to translate this potential into everyday dental practice. The promising future of PDT in dentistry suggests a more effective and less invasive treatment option for a range of dental conditions.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117962"},"PeriodicalIF":3.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis and biological evaluation of novel oxazole derivatives as potential hypoglycemic agents 作为潜在降糖药的新型噁唑衍生物的设计、合成和生物学评价。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-18 DOI: 10.1016/j.bmc.2024.117961

Ruifeng Wang , Ke Chen , Shuihua Liu , Ruyue Ren , Hongbao Hou , Qingxuan Zeng , Yi Zhang , Yunfeng Liu

引用次数: 0

Discovery of cyanoguanidine derivatives as biased μ-opioid receptor agonists 发现氰基胍衍生物作为有偏倚的μ-阿片受体激动剂。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-16 DOI: 10.1016/j.bmc.2024.117943

Liang-han Zhu , Hui-huan Mao , Mingchao He , Zhi-ying Cui , Qi-hua Zhu , Hong-feng Gu , Yun-gen Xu

引用次数: 0

Synthesis and biological evaluation of novel isobenzofuran-1(3H)-one derivatives as antidepressant agents 作为抗抑郁剂的新型异苯并呋喃-1(3H)-酮衍生物的合成和生物学评价。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-16 DOI: 10.1016/j.bmc.2024.117941

Liu Tao , Chuanjie Yao , Sijie Wang , Yuying Ye , Zhengchao Tu , Xiaojian Jiang , Lipeng Xu , Luchen Shan , Zheng Liu , Pei Yu

{"title":"Synthesis and biological evaluation of novel isobenzofuran-1(3H)-one derivatives as antidepressant agents","authors":"Liu Tao , Chuanjie Yao , Sijie Wang , Yuying Ye , Zhengchao Tu , Xiaojian Jiang , Lipeng Xu , Luchen Shan , Zheng Liu , Pei Yu","doi":"10.1016/j.bmc.2024.117941","DOIUrl":"10.1016/j.bmc.2024.117941","url":null,"abstract":"<div><div>A series of novel isobenzofuran-1(3<em>H</em>)<em>-</em>one derivatives were designed and synthesized as antidepressants. Firstly, the serotonin reuptake inhibition of these compounds was tested <em>in vitro,</em> and most of them exhibited activity. Particularly, compounds <strong>9d</strong>, <strong>10a</strong>, and <strong>10c</strong> demonstrated superior inhibitory effects and possibly avoided addiction via the μ-opioid receptor and CCK-B receptor. Secondly, the antidepressant effect of compound <strong>10a</strong> was evaluated using chronic restraint stress (CRS)-induced mice. The results showed that compound <strong>10a</strong> significantly improved CRS-induced depression-like behavior by increasing the neurotransmitters 5-HT in the cortex and THP2 expression in the hippocampus. Thirdly, compound <strong>10a</strong> was further investigated and found to enhance CRS-induced hippocampal neuron damage recovery and elevate the expression of synaptic-associated proteins such as BDNF, TrkB, PSD95, and Spinophilin in CRS-induced mice. These findings suggested that novel isobenzofuran-1(3<em>H</em>)<em>-</em>one derivative showed efficacy in treating depression, with compound <strong>10a</strong> emerging as a potential lead compound warranting further investigation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117941"},"PeriodicalIF":3.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 4,6-diarylquinoxaline-based KDM4D inhibitors 基于 4,6-二芳基喹喔啉的 KDM4D 抑制剂的设计、合成和生物学评价。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-16 DOI: 10.1016/j.bmc.2024.117945

Dongxuan Ni , Xuechun Chen , Hairong Wang , Tianze Shen , Xiaoli Li , Bin Liang , Ruihan Zhang , Rong Liu , Weilie Xiao

引用次数: 0