Bioorganic & Medicinal Chemistry最新文献_第10页

Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor 通过联合使用 PARP1-PROTAC 和 BRD4 抑制剂提高同源重组缺陷胰腺癌的疗效。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-26 DOI: 10.1016/j.bmc.2024.117970

Chunlan Pu , Yuanyuan Liu , Suke Lan , Hengrui Fan , Lvye Liu , Jianyu Liu , Yuanbiao Guo

Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Repression of bromodomain-containing protein 4 (BRD4) can block the homologous recombination (HR) repair pathway and has the potential to enhance the response to PARPi in HR-proficient pancreatic cancer therapy. In addition, proteolysis targeting chimeras (PROTACs) can hijack E3 ligase within the cell to ubiquitinate degradation-targeted proteins effectively and quickly, thus enhancing the therapeutic effect on tumors. In the present study, the LB23 compound, which induces PARP1 degradation, was employed in combination with the BRD4 inhibitor JQ1, confirming their synergistic effect in HR-proficient pancreatic cancer through various methods. Moreover, compared to the JQ1 and PARPi olaparib combination, PARP1-PROTAC and JQ1 had more notable synergistic effects. Further research into the synergistic mechanism demonstrated that combination therapy enhanced DNA damage and suppressed DNA repair by inducing cell cycle arrest and cell apoptosis. The present study therefore provides the experimental data for this type of combination therapy, which is expected to be an innovative approach for the treatment of HR-proficient pancreatic cancer.

目前，美国食品和药物管理局已批准将多（ADP-核糖）聚合酶抑制剂（PARPi）用于治疗 BRCA 基因突变的胰腺癌。然而，有限的适应症阻碍了它们的进一步应用。抑制含溴结构域蛋白 4（BRD4）可阻断同源重组（HR）修复途径，并有可能增强 HR 特异性胰腺癌治疗对 PARPi 的反应。此外，蛋白水解靶向嵌合体（PROTACs）可以劫持细胞内的E3连接酶，有效、快速地泛素化降解靶向蛋白，从而增强对肿瘤的治疗效果。在本研究中，诱导PARP1降解的LB23化合物与BRD4抑制剂JQ1联用，通过多种方法证实了它们在HR缺陷型胰腺癌中的协同作用。此外，与JQ1和PARPi olaparib联用相比，PARP1-PROTAC和JQ1的协同作用更为显著。对协同作用机制的进一步研究表明，联合疗法通过诱导细胞周期停滞和细胞凋亡，增强了DNA损伤，抑制了DNA修复。因此，本研究为这种联合疗法提供了实验数据，有望成为治疗HR阳性胰腺癌的一种创新方法。

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引用次数: 0

Discovery and optimization of anthraquinone derivatives containing substituted bisbenzyloxy groups as a novel scaffold damaged endoplasmic reticulum and against hepatocellular carcinoma cells 发现并优化含有取代的双苄氧基基团的蒽醌衍生物，将其作为损伤内质网和抗肝癌细胞的新型支架

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-26 DOI: 10.1016/j.bmc.2024.117969

Xiaoyan Shen , Honglan Zhai , Wei Tian , Linfang Lai , Tuo Ma , Xuyang Chen , Chunmiao Wang , Huaxin Hou

This paper reports the antitumor activity and possible mechanism of anthraquinone derivatives containing substituted bisbenzyloxy groups. Series of anthraquinone derivatives containing substituted bisbenzyloxy groups were designed and synthesized by etherification and esterification. The antitumor activities of the synthesized substituted bisbenzyloxy anthraquinone derivatives on liver cancer cell Huh7, triple negative breast cancer cell line MDA-MB-231 and lung cancer cell A549 were in the order of methoxy substitution > methyl substitution > chloral substitution. Among these, the Compound KA-MO-g showed strong antitumor activity, especially against liver cancer Huh7 cells. Further studies on the antitumor mechanism showed that the Compound KA-MO-g simultaneously activated three pathways of endoplasmic reticulum stress (ERS), also caused impairment of endoplasmic reticulum (ER) functions, such as glycoprotein synthesis and disulfide bond formation are impeded and caused calcium overload, then increased mitochondrial ROS, damaged of mitochondria, changed of apoptosis-related protein levels, activated Caspase 3, induced the apoptosis of Huh7 cells. Because KA-MO-g showed strong antitumor activity, it is expected to be a new candidate drug for treating liver cancer and is worth further study.

本文报告了含有取代的双苄氧基基团的蒽醌衍生物的抗肿瘤活性和可能的机理。本文设计并通过醚化和酯化反应合成了一系列含有取代双苄氧基的蒽醌衍生物。合成的取代双苄氧基蒽醌衍生物对肝癌细胞Huh7、三阴性乳腺癌细胞株MDA-MB-231和肺癌细胞A549的抗肿瘤活性依次为甲氧基取代> 甲基取代> 氯醛取代。其中，化合物 KA-MO-g 表现出很强的抗肿瘤活性，尤其是对肝癌 Huh7 细胞。对其抗肿瘤机制的进一步研究表明，化合物 KA-MO-g 同时激活了内质网应激（ERS）的三条通路，还导致内质网（ER）功能受损，如糖蛋白合成和二硫键形成受阻，引起钙超载，进而增加线粒体 ROS，破坏线粒体，改变凋亡相关蛋白水平，激活 Caspase 3，诱导 Huh7 细胞凋亡。由于KA-MO-g具有很强的抗肿瘤活性，有望成为治疗肝癌的一种新的候选药物，值得进一步研究。

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引用次数: 0

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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-26 DOI: 10.1016/j.bmc.2024.117967

Chao Zhang , Xiuyun Sun , Peilu Song , Yu Rao

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.

免疫炎症性疾病是一类发病率很高的疾病，严重影响患者的生活质量。目前的治疗策略包括免疫抑制剂、糖皮质激素和单克隆抗体。然而，这些方法都有一定的局限性，如膜渗透性差、免疫原性以及大分子药物需要注射等。而小分子化合物则存在选择性差、无法抑制非酶功能和生物补偿等问题。这些因素制约了当前免疫炎症性疾病治疗策略的有效性。作为一种新型小分子药物开发技术，蛋白水解靶向嵌合体（PROTACs）通过诱导靶蛋白与 E3 泛素连接酶之间的相互作用来调节蛋白水平，从而导致靶蛋白的选择性降解。这项技术在治疗免疫炎症性疾病方面已显示出良好的治疗效果。本综述旨在全面总结 PROTAC 技术在免疫炎症领域的应用，并深入探讨其在治疗免疫炎症疾病方面的潜力。

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

The 3₁₀-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 3₁₀-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 3₁₀-helices. Circular dichroism spectroscopy revealed that the R_i_,_i₊₃S(4) staple—a 4-atom cross-link with (R)-configuration at the i position, (S)-configuration at the i + 3 position, and flanked by methyl groups—strongly induces right-handed 3₁₀-helices, especially in sequences with proteinogenic l-amino acids. Furthermore, multiple staples effectively stabilized longer peptides, underscoring the versatility of this approach for applications in peptide therapeutics and biomolecular engineering.

310 螺旋是蛋白质中一种重要的二级结构，在各种蛋白质-蛋白质相互作用中发挥着至关重要的作用，然而在具有生物相关性的肽中稳定这种结构仍然具有挑战性。在本研究中，我们研究了 4 原子碳氢化合物主链稳定肽中 310 螺旋的潜力。通过闭环偏析，我们证明了主链的构型对于 310-helices的稳定和螺杆感控制至关重要。环二色性光谱显示，Ri,i+3S(4) 主链--一种在 i 位具有 (R) 构型、在 i + 3 位具有 (S) 构型、两侧有甲基的 4 原子交联--能强烈诱导右旋 310 螺旋，尤其是在含有蛋白质源 l- 氨基酸的序列中。此外，多重主链还能有效稳定较长的肽段，突出了这种方法在肽治疗和生物分子工程中应用的多样性。

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-22 DOI: 10.1016/j.bmc.2024.117966

Mayank Kashyap, Saurabh Gupta, Yogita Bansal, Gulshan Bansal

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.

血管内皮生长因子（VEGFs）是一类同源二聚体配体，可与其受体（VEGFRs）结合，进行生理性和病理性血管生成，对调节体内平衡至关重要。血管内皮生长因子的过度表达会导致良性肿瘤转移为恶性肿瘤。VEGFR-2 在癌症血管生成中的积极作用使其成为癌症治疗的主要靶点。美国 FDA 批准的 VEGFR-2 抑制剂如索拉非尼（sorafenib）、维莫非尼（vemurafenib）和达拉菲尼（dabrafenib），以及单克隆抗体如贝伐珠单抗（bevacizumab）和雷莫单抗（ramucirumab）已在市场上销售，但它们都有副作用，如高血压、CVS 紊乱、肝损伤和先天性不良反应等。全球已有多个研究小组根据受体活性位点的信息和美国 FDA 批准药物的药效学特征，设计并报道了不同杂核（如喹唑啉、嘧啶、香豆素、吡唑、吲哚啉、苯并咪唑、苯并恶唑等）的各种小分子作为 VEGFR-2 抑制剂。本综述汇编了近年来有关苯并咪唑、苯并恶唑和苯并噻唑等苯并杂核化合物的信息，重点介绍了这些化合物的设计、活性、结构-活性关系（SAR）和对接分析，以了解 VEGFR-2 活性位点的结合相互作用。此外，还以索拉非尼为模板，对这些化合物进行了拓扑相似性分析，并提出了全面的 SAR，供研究人员进一步探索这些药源的抗癌潜力。

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

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.

芳基烃受体（AhR）是一种由配体激活的细胞转录因子，与各种生理和病理过程密不可分。在其多种配体中，吲哚类化合物因其显著的生物活性和潜在的治疗应用而备受关注。本研究探讨了不同结构的卤代吲哚对 AhR 的激活作用。我们评估了人 LS174T-AhR-luc 报告细胞系中 AhR 的转录活性和细胞活力。在测试的化合物中，4-FI、7-FI、6-BrI、7-BrI、6-Cl-2-ox、5-Br-2-ox 和 6-Br-2-ox 以浓度依赖的方式激活 AhR，显示出较高的效力和有效性。分子对接分析表明，这些化合物与 AhR 的 PAS-B 结构域有适度的结合亲和力，竞争性放射性配体结合试验也证实了这一点。功能测定显示，卤代吲哚能诱导形成 AhR-ARNT 异源二聚体，并增强 AhR 与 CYP1A1 启动子的结合。此外，4-FI 和 7-FI 在 Caco-2 细胞模型中表现出抗炎特性，突显了它们的治疗应用潜力。这项研究强调了吲哚支架中卤素分子的类型和位置的重要性，表明它们具有开发治疗药物的潜力，可通过激活 AhR 治疗炎症性肠病等疾病。

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

Src Homology 2-containing Inositol 5′-Phosphatase-1 (SHIP-1), encoded by INPP5D, 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 IC₅₀s 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 IC₅₀ value of 6.1 μM. Kinetic analyses of SP3-12 revealed that its inhibition mechanism is competitive, with a K_i 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 EC₅₀ 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.

由 INPP5D 编码的 Src 同源体 2-含肌醇 5'-磷酸酶-1（SHIP-1）通过最近的遗传学和表观遗传学研究被确定为阿尔茨海默病（AD）的风险相关基因。SHIP-1 通过抑制 TREM2 级联和减少有益的微神经胶质细胞过程（包括吞噬作用）来增加阿尔茨海默病的风险。虽然有报道称几种小分子可以调节 SHIP-1 的活性，但它们在高级模型中有限的选择性和有效性限制了它们作为治疗药物或生物学研究探针的潜力。在此，我们验证并实施了一个高通量筛选平台，以探索能调节 SHIP-1 磷酸酶活性的新化学型。我们使用基于孔雀石绿的抗 SHIP-1 活性测定法筛选了 49,260 种来自商业供应商的中枢神经系统 (CNS) 蛋白化合物。通过对筛选结果的分析、优先排序和验证，我们发现了三种新型支架，它们能抑制 SHIP-1 磷酸酶的活性，IC50 低至 46.6 µM。为了提高这些有希望的新发现的抑制活性，我们进行了结构-活性关系（SAR）研究，最终发现了一种先导分子 SP3-12，它抑制 SHIP-1 的 IC50 值为 6.1 μM。SP3-12 的动力学分析表明，其抑制机制是竞争性的，对 SHIP-1 的 Ki 值为 3.2 µM，对 SHIP-2 的选择性为 7 倍。此外，在小胶质细胞吞噬/细胞健康高含量试验中的测试结果表明，SP3-12 能有效激活人小胶质细胞克隆 3 (HMC3) 细胞的吞噬功能，EC50 为 2.0 µM，在剂量范围内无细胞毒性。鉴于其效力、选择性和细胞活性，SP3-12 成为一种有潜力研究 SHIP-1 生物功能的小分子抑制剂。

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

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.

光动力疗法（PDT）是一种发展迅速的非侵入性治疗方式，在牙科药物治疗中大有可为。这篇综述文章全面探讨了光动力疗法，首先介绍了其原理，然后深入探讨了它在牙科中的各种应用，包括牙周病、牙髓病、口腔癌、牙种植体和龋齿。每个领域都介绍了最新的研究成果，并讨论了潜在的益处和挑战。其中强调了光敏剂的独特优势，如选择性靶向、广谱抗菌作用、不产生抗药性以及与其他治疗方法的协同作用。然而，光敏剂输送、光穿透、氧气供应以及标准化方案的必要性等挑战也得到了认可。综述进一步探讨了光动力疗法在牙科中的未来前景，包括光敏剂设计的进步、克服缺氧限制、个性化方案、与其他疗法的整合以及标准化和监管。此外，还讨论了先进技术（如纳米技术和合成生物学）在改善 PDT 治疗效果方面的潜力。综述的结论是，虽然光动力疗法在牙科药物治疗方面显示出巨大的变革潜力，但要将这种潜力转化为日常的牙科实践，还需要进一步的高质量研究。PDT在牙科领域的发展前景广阔，为一系列牙科疾病提供了更有效、创伤更小的治疗方案。

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

A series of 2,4-disubstituted-oxazole derivatives have been designed and synthesized based on compound 3a, a promising lead compound developed in our lab. Among these derivatives, the optimized compound 5k exhibited potent hypoglycemic activity, increasing glucose consumption by 60 % in HepG2 cells compared to the solvent control, and its activity was higher than that of metformin. Further investigation indicated that compound 5k exhibited negligible cytotoxic effects at a concentration of 25 μM in HepG2 and 3T3-L1 cells and showed moderate inhibitory activity against various subtypes of human cytochrome P450 subtypes. An oral glucose tolerance test confirmed that 5k is an effective hypoglycemic agent. Additionally, mechanistic studies suggested that 5k may exert its hypoglycemic activity through the activation of the AMPK pathway.

以我们实验室开发的前景看好的先导化合物 3a 为基础，设计并合成了一系列 2,4-二取代噁唑衍生物。在这些衍生物中，优化后的化合物 5k 表现出了强效的降血糖活性，与溶剂对照相比，它能使 HepG2 细胞的葡萄糖消耗量增加 60%，其活性高于二甲双胍。进一步的研究表明，当浓度为 25 μM 时，化合物 5k 在 HepG2 和 3T3-L1 细胞中的细胞毒性作用可忽略不计，并且对人类细胞色素 P450 的各种亚型具有中等程度的抑制活性。口服葡萄糖耐量试验证实 5k 是一种有效的降血糖药。此外，机理研究表明，5k 可能通过激活 AMPK 途径发挥降血糖活性。

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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

Opioid agonists, including morphine and its derivatives, have historically been utilized in conventional pain relief therapies. However, the morphine-like side effects associated with these compounds have constrained their broader application in clinical environments. Fortunately, novel compounds that selectively activate μ-opioid receptors (MOR) without activating the β-arrestin2 pathway, such as PZM21 and TRV130, demonstrate the potential to mitigate side effects while maintaining analgesic efficacy. In this study, we structurally modified PZM21 to get a series of compounds with a 2-cyanoguanidine scaffold, the majority of which display significant analgesic effects. Notably, Compound I-11 exhibited an analgesic effect comparable to that of morphine and selectively activates μ-opioid receptors while avoiding the activation of the β-arrestin2 pathway. Our work not only introduces a novel biased μ-opioid receptor agonist but also serves as a valuable reference for the further optimization of PZM21.

包括吗啡及其衍生物在内的阿片类受体激动剂历来被用于传统的止痛疗法。然而，与这些化合物相关的吗啡样副作用限制了它们在临床环境中的广泛应用。幸运的是，选择性激活μ-阿片受体（MOR）而不激活β-阿司匹林2通路的新型化合物，如PZM21和TRV130，展示了在保持镇痛疗效的同时减轻副作用的潜力。在这项研究中，我们对 PZM21 进行了结构修饰，得到了一系列具有 2-氰基胍支架的化合物，其中大多数化合物都具有显著的镇痛效果。值得注意的是，化合物 I-11 显示出与吗啡相当的镇痛效果，并能选择性地激活μ-阿片受体，同时避免激活β-arrestin2 通路。我们的研究不仅推出了一种新型偏性μ-阿片受体激动剂，还为进一步优化PZM21提供了有价值的参考。

引用次数: 0