JAK抑制剂因能够抑制JAK/STAT信号通路从而治疗炎症和自身免疫疾病,逐渐成为药物研究领域的热点,但面对庞大的潜在药物分子如何有效地筛选从而得到有效的药物分子仍然面临着挑战。因此通过计算机辅助处理分子信息,并结合分子对接、药代...JAK抑制剂因能够抑制JAK/STAT信号通路从而治疗炎症和自身免疫疾病,逐渐成为药物研究领域的热点,但面对庞大的潜在药物分子如何有效地筛选从而得到有效的药物分子仍然面临着挑战。因此通过计算机辅助处理分子信息,并结合分子对接、药代动力学、分子动力学、机器学习等相关技术进行药物分子的虚拟筛选从而为接下来的药物合成,生物测试等提供重要的研究思路,本文主要综述使用计算机辅助药物设计技术在JAK小分子抑制剂研究中的相关进展,介绍其相关的设计思路,并对计算机辅助药物设计的发展前景做出展望。JAK inhibitors, which can suppress the JAK/STAT signaling pathway to treat inflammatory and autoimmune diseases, have gradually become a hot topic in the field of drug research. However, faced with a vast number of potential drug molecules, effectively screening to obtain effective drug molecules still poses a significant challenge. Therefore, by using computer-aided processing of molecular information, combined with related technologies such as molecular docking, pharmacokinetics, molecular dynamics, and machine learning, to conduct virtual screening of drug molecules, important research ideas are provided for subsequent drug synthesis and biological testing. This article mainly reviews the advancements in the research of JAK small molecule inhibitors using computer-aided drug design techniques, introduces the related design concepts, and offers a perspective on the future development of computer-aided drug design.展开更多
目的:将微管蛋白抑制剂康普瑞汀(Combretastatin A4, CA4)的顺式二苯乙烯结构改造为偶氮苯类化合物,以其体内分布的特异性活化性能来增强其靶向性。方法:以3,4,5-三甲氧基苯胺为起始原料,经过重氮化反应后,与邻炔丙氧基苯酚进行偶合,得...目的:将微管蛋白抑制剂康普瑞汀(Combretastatin A4, CA4)的顺式二苯乙烯结构改造为偶氮苯类化合物,以其体内分布的特异性活化性能来增强其靶向性。方法:以3,4,5-三甲氧基苯胺为起始原料,经过重氮化反应后,与邻炔丙氧基苯酚进行偶合,得到关键中间体AzO-OH;关键中间体进一步与碘甲烷、溴丙烷或溴代正丁烷在K2CO3存在下进行酚羟基的取代反应,得到产物AzO-Me,AzO-Pr,AzO-Bu。结果:设计并合成得到CA4的偶氮化衍生物,其结构经NMR、MS确证;分子对接表明,该类化合物与微管蛋白具有较强的结合性,其结合模式与顺式CA4相近,因而可能具有类似或更强的微管蛋白抑制作用;光学性能研究发现,该类偶氮化合物在不同波长光照下会发生顺-反或反-顺的构型变化;初步的药理实验的结果显示,细胞增殖抑制活性在光照后大大提高。结论:将CA4改造为偶氮苯类化合物后,通常情况下以无生物活性但性质更稳定的反式结构存在,而在体内靶部位给予特定波段的光,就可以转化为具有活性的顺式结构发挥作用,从而可以实现“全身给药,局部激活”的靶向性能,加强了CA4的靶向性,初步的药理实验证实了上述设想。Objective: To transform the cis-stilbene structure of the tubulin inhibitor Combretastatin A4 (CA4) into an azobenzene compound, so as to enhance its targeting ability in vivo. Method: The starting material 3,4,5-trimethoxyaniline was diazotized, then coupling with o-propargyloxyphenol to obtain the key intermediate AzO-OH;the key intermediate was further substituted with the reaction of the phenolic hydroxyl group to obtain the product AzO-Me, AzO-Pr, AzO-Bu, by combining with methyl iodide, bromopropane or bromo-n-butane in the presence of K2CO3. Results: The azo derivatives of CA4 were synthesized. Their structures were confirmed by NMR and MS. Molecular docking showed that these compounds had strong binding activities to tubulin, and the binding modes were similar to that of cis-CA4. So they may have a similar or stronger inhibitory effect on tubulin. Optical performance studies have found that this type of azo compound undergoes a cis to trans or trans to cis configuration changes under different wavelengths of light. The results of preliminary pharmacological experiments showed that the inhibitory activity of cell proliferation was greatly improved after illumination. Conclusions: After transforming CA4 into azobenzene compound, it usually exists as a stable trans-structure with no or little biological activity. However, given a specific wavelength of light at the target site in the body, it can be converted into an active cis-form. The structure plays an important role, so that the targeting performance of “systemic administration, local activation” can be realized, and the targeting ability of CA4 can be enhanced. Preliminary pharmacological experiments confirmed the hypothesis.展开更多
本研究以胶凝时间为评价指标,通过单因素试验法考察了连翘温敏口腔凝胶中泊洛沙姆407 (F127)、泊洛沙姆188 (F68)和丙三醇的配比对胶凝时间的影响,以响应面法优化了该凝胶的制备工艺。采用目测法观察连翘温敏口腔凝胶的性状和外观,pH试...本研究以胶凝时间为评价指标,通过单因素试验法考察了连翘温敏口腔凝胶中泊洛沙姆407 (F127)、泊洛沙姆188 (F68)和丙三醇的配比对胶凝时间的影响,以响应面法优化了该凝胶的制备工艺。采用目测法观察连翘温敏口腔凝胶的性状和外观,pH试纸测定其pH值,恒温水浴中测定胶凝时间和胶凝温度,采用透析袋法,以PBS缓冲液为释放基质,考察了该凝胶的体外释药性能。结果表明,连翘温敏口腔凝胶的最优配比为F127含量17%、F68含量6%、丙三醇含量4%。该连翘温敏口腔凝胶为橘黄色均一透明具凝胶特性的稠厚液体,pH值为6.5~6.8,均一性良好,胶凝温度为35 ± 0.2℃,胶凝时间为10.5 ± 0.1 s。体外释放试验结果表明该凝胶在释放介质中展现出了良好的缓释性能。In this study, forsythia thermosensitive oral gel was prepared and the preparation process was optimized. Single factor experiment was conducted to explore the influence of the ratio of Poloxam 407 (F127), Poloxam 188 (F68), and glycerol in forsythia thermosensitive oral gel on the gel time, and response surface method was used to optimize the preparation process of the gel. The characteristics and appearance of forsythia thermosensitive oral gels were observed by visual method, pH values were determined by pH test paper, gel time and gel temperature were determined in a constant temperature water bath. The in vitro release performance of forsythoside A in the gels was investigated by the dialysis bag method with PBS buffer used as the release medium. According to the analysis of the overall experimental study, the optimal proportions of the gels were obtained as follows: the ratio of Poloxham 407 was 17%, Poloxham 188 was 6% and glycerol was 4%. The prepared forsythia thermosensitive oral gel was orange, transparent and gel thick liquid, pH value was 6.5~6.8, the uniformity is good, gel temperature was 35 ± 0.2˚C, and gel time was 10.5 ± 0.1 s. In vitro release experiments results showed that the prepared gels exhibited good sustained-release performance in the provided release medium.展开更多
[目的]本研究基于网络药理学与分子对接技术,系统探讨三叶青对动脉粥样硬化的潜在抗病机制,明确其主要有效成分、作用靶点及相关信号通路,为三叶青的药理作用研究提供理论依据。[方法]通过TCMSP数据库并结合特定筛选条件,确定三叶青的...[目的]本研究基于网络药理学与分子对接技术,系统探讨三叶青对动脉粥样硬化的潜在抗病机制,明确其主要有效成分、作用靶点及相关信号通路,为三叶青的药理作用研究提供理论依据。[方法]通过TCMSP数据库并结合特定筛选条件,确定三叶青的主要有效成分及其对应的靶点,并构建“有效成分–靶点网络”。进一步利用GeneCards和OMIM数据库筛选与动脉粥样硬化相关的疾病靶点,从中获取药物靶点与疾病靶点的交集。在此基础上,对交集靶点进行蛋白质互作(PPI)网络分析、基因本体(GO)生物功能富集分析和KEGG信号通路富集分析。同时应用Cytoscape 3.7.2软件中的“Analyze Network”工具,构建“有效成分–靶点–通路”网络。最后,通过分子对接方法验证关键有效成分与核心靶点之间的亲和力。[结果]筛选出三叶青的9种主要有效成分,其中7种成分与靶点具有明确的对应关系,而2种因药代动力学而舍弃。通过分析获得2084个与动脉粥样硬化相关的疾病靶点,并筛选出77个药物靶点与疾病靶点的交集。PPI网络分析显示,AKT1、PPARG、PTGS2、EGFR和ESR1等是主要的核心靶点。GO生物功能富集分析中,共获得285个与生物过程相关的条目、44个与细胞成分相关的条目以及108个与分子功能相关的条目。KEGG信号通路富集分析筛选出108条显著富集的信号通路,主要涉及内分泌抵抗、EGFR酪氨酸激酶抑制剂耐药性以及花生四烯酸代谢等关键通路。分子对接结果显示,槲皮素、山柰素、异鼠李素和山奈酚与AKT1靶点具有较高的结合亲和力,表明这些成分可能是三叶青发挥药理作用的核心成分。[结论]研究结果表明,三叶青中的核心有效成分槲皮素、山柰素、异鼠李素和山奈酚可能通过调控脂质代谢与动脉粥样硬化相关的关键信号通路,作用于核心靶点AKT1,从而在蛋白质结合、酶结合及可识别蛋白结合等生物学功能中发挥抗动脉粥样硬化的作用。本研究为三叶青的进一步开发和利用提供了理论支持。Aim: This study systematically investigates the potential anti-atherosclerotic mechanisms of Tetrastigma hemsleyanum (San Ye Qing) using network pharmacology and molecular docking approaches. It aims to identify the primary active components, potential targets, and associated signaling pathways, providing a theoretical foundation for the pharmacological research of Tetrastigma hemsleyanum. Methods: The main active components of Tetrastigma hemsleyanum and their corresponding targets were identified through the TCMSP database with specific screening criteria, and the “active component-target network” was constructed. Subsequently, disease targets related to atherosclerosis were retrieved from the GeneCards and OMIM databases, and the intersection of drug targets and disease targets was obtained. Protein-protein interaction (PPI) network analysis, Gene Ontology (GO) biological function enrichment analysis, and KEGG pathway enrichment analysis were performed on the intersected targets. The “active component-target-pathway network” was constructed using the Analyze Network tool in Cytoscape 3.7.2. Finally, molecular docking was employed to verify the binding affinity between key active components and core targets. Results: Nine major active components of Tetrastigma hemsleyanum were identified, seven of which had clear corresponding targets, while two were excluded due to poor pharmacokinetic properties. A total of 2084 disease-related targets for atherosclerosis were obtained, with 77 overlapping targets identified as the intersection of drug and disease targets. PPI network analysis revealed that AKT1, PPARG, PTGS2, EGFR, and ESR1 were the primary core targets. GO enrichment analysis identified 285 biological process terms, 44 cellular component terms, and 108 molecular function terms. KEGG pathway enrichment analysis revealed 108 significantly enriched signaling pathways, primarily involving endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and arachidonic acid metabolism. Molecular docking demonstrated that quercetin, kaempferol, isorhamnetin, and kaempferide exhibited strong binding affinities to the core target AKT1, suggesting that these components may be the key active ingredients of Tetrastigma hemsleyanum. Conclusion: The results suggest that the core active components of quercetin, kaempferol, isorhamnetin, and kaempferide in Tetrastigma hemsleyanum may exert anti-atherosclerotic effects by regulating key signaling pathways related to lipid metabolism and atherosclerosis, such as the MAPK signaling pathway. These components likely act on the core target AKT1 to mediate biological functions such as protein binding, enzyme binding, and protein recognition. This study provides a theoretical basis for the further development and utilization of Tetrastigma hemsleyanum.展开更多
本文借助密度泛函理论中的B3LYP算法,基于6-31G(d)理论基组,深入探讨了甲氧氯普胺分子的结构特性,成功获取了其稳定的分子构象及红外光谱属性。研究揭示,甲氧氯普胺的红外振动光谱因振动模式的差异,主要分布于三个频率范围:低频段(0~500...本文借助密度泛函理论中的B3LYP算法,基于6-31G(d)理论基组,深入探讨了甲氧氯普胺分子的结构特性,成功获取了其稳定的分子构象及红外光谱属性。研究揭示,甲氧氯普胺的红外振动光谱因振动模式的差异,主要分布于三个频率范围:低频段(0~500) cm−1、中频段(500~2000) cm−1和高频段(2000~4000) cm−1。此外,由于简并振动及非红外活性振动的存在,实际红外光谱中可辨识的谱线少于理论预测的简正振动数目。In this paper, the B3LYP algorithm within Density Functional Theory (DFT), based on the 6-31G(d) theoretical basis set, is employed to delve into the structural characteristics of the metoclopramide molecule. Stable molecular conformations and infrared spectral properties of metoclopramide are successfully obtained. The study reveals that the infrared vibrational spectrum of metoclopramide is mainly distributed across three frequency ranges due to different vibrational modes: the low-frequency range (0~500) cm−1, the mid-frequency range (500~2000) cm−1, and the high-frequency range (2000~4000) cm−1. Additionally, due to the presence of degenerate vibrations and non-infrared-active vibrations, the number of identifiable spectral lines in the actual infrared spectrum is less than the number of normal vibrations theoretically predicted.展开更多
本文详述了一项针对二肽基肽酶4 (DPP4)靶点的创新药物研发策略,该策略通过整合虚拟筛选、分子对接与分子动力学模拟三大前沿技术,实现了药物研发效率与精度的双重提升。研究从大型化合物库出发,运用先进算法与机器学习工具高效筛选出与...本文详述了一项针对二肽基肽酶4 (DPP4)靶点的创新药物研发策略,该策略通过整合虚拟筛选、分子对接与分子动力学模拟三大前沿技术,实现了药物研发效率与精度的双重提升。研究从大型化合物库出发,运用先进算法与机器学习工具高效筛选出与DPP4靶点具有潜在高结合亲和力的候选分子,大幅缩减实验候选范围。随后,采用分子对接技术深入剖析候选分子与靶点的相互作用模式、能量特征及关键氨基酸残基的作用机制,成功筛选出高亲和力、高选择性的先导化合物。为进一步验证与优化,研究引入分子动力学模拟,动态观测候选药物在生物环境中的构象稳定性、溶剂化效应及与靶点的动态结合,为药物设计提供了科学依据,加速了DPP4抑制剂的研发进程,为糖尿病及其他代谢性疾病的治疗开辟了新前景。This paper details an innovative drug development strategy targeting dipeptidyl peptidase-4 (DPP4), which integrates three cutting-edge technologies: virtual screening, molecular docking, and molecular dynamics simulations. This strategy enhances both the efficiency and accuracy of drug development. The study begins with a large compound library, employing advanced algorithms and machine learning tools to efficiently screen for candidate molecules with potential high binding affinity to the DPP4 target, significantly narrowing down the pool of experimental candidates. Subsequently, molecular docking techniques are used to deeply analyze the interaction patterns, energy characteristics, and the role of key amino acid residues between the candidate molecules and the target, successfully identifying lead compounds with high affinity and selectivity. To further validate and optimize, the study incorporates molecular dynamics simulations to dynamically observe the conformational stability, solvation effects, and dynamic binding with the target in a biological environment. This provides scientific evidence for drug design, accelerates the development of DPP4 inhibitors, and opens new prospects for the treatment of diabetes and other metabolic diseases.展开更多
在过去的二十年里,随着IMiD和indisulam等MG降解剂的出现,分子胶(MGs)逐渐引起了制药界的关注。这些分子通过促进靶蛋白和E3连接酶之间的相互作用来降解靶蛋白。此外,MGs作为化学诱导剂,促进同源蛋白和异源蛋白的二聚化形成三元复合物,...在过去的二十年里,随着IMiD和indisulam等MG降解剂的出现,分子胶(MGs)逐渐引起了制药界的关注。这些分子通过促进靶蛋白和E3连接酶之间的相互作用来降解靶蛋白。此外,MGs作为化学诱导剂,促进同源蛋白和异源蛋白的二聚化形成三元复合物,在调节生物活性方面具有很大的前景。本文重点介绍MGs在药物开发领域的应用,包括蛋白质–蛋白质相互作用(PPI)稳定性和蛋白质降解。我们深入分析了各种MGs的结构以及MGs与各种生物活性分子之间的相互作用,从而为PPI稳定剂和新型降解剂的开发提供了新的视角。Over the past two decades, molecular glues (MGs) have gradually attracted the attention of the pharmaceutical community with the advent of MG degraders such as IMiDs and indisulam. Such molecules degrade the target protein by promoting the interaction between the target protein and E3 ligase. In addition, as a chemical inducer, MGs promote the dimerization of homologous proteins and heterologous proteins to form ternary complexes, which have great prospects in regulating biological activities. This review focuses on the application of MGs in the field of drug development including protein-protein interaction (PPI) stability and protein degradation. We thoroughly analyze the structure of various MGs and the interactions between MGs and various biologically active molecules, thus providing new perspectives for the development of PPI stabilizers and new degraders.展开更多
目的:探索硫糖铝对小鼠放射性口腔黏膜炎(radiation-induced oral mucositis;RIOM)的治疗效果及其可能机制。材料和方法:建立小鼠RIOM模型,从小鼠辐照完成后至处死小鼠期间,每日使用硫糖铝局部涂抹小鼠舌背,观察溃疡情况,并行组织病理学...目的:探索硫糖铝对小鼠放射性口腔黏膜炎(radiation-induced oral mucositis;RIOM)的治疗效果及其可能机制。材料和方法:建立小鼠RIOM模型,从小鼠辐照完成后至处死小鼠期间,每日使用硫糖铝局部涂抹小鼠舌背,观察溃疡情况,并行组织病理学和WB检测。结果:18 Gy γ射线大剂量一次性照射头颈部后第9天小鼠舌部出现明显的溃疡。与单纯辐照组相比,硫糖铝处理组小鼠舌背溃疡面积较小,舌背黏膜基底层细胞更多,组织内促凋亡蛋白Bax和Caspase-3水平显著降低,抗凋亡蛋白Bcl-2水平显著升高。结论:使用硫糖铝治疗能改善RIOM小鼠的舌背黏膜情况,推测可能是通过形成局部屏障、促进细胞增殖、抗细胞凋亡、清除自由基等方面作用从而减轻口腔黏膜局部炎症,促进黏膜炎愈合。Purpose: To investigate the therapeutic effects of sucralfate on radiation-induced oral mucositis (RIOM) in mice and explore its potential mechanisms. Materials and Methods: A mouse model of RIOM was established. From the completion of irradiation until euthanasia, sucralfate was topically applied to the dorsal tongue of mice daily. Ulcer conditions were observed, and histopathological and Western blot (WB) analyses were performed. Results: On the 9th day after a single high-dose (18 Gy) γ-ray irradiation of the head and neck, significant ulcers appeared on the tongues of mice. Compared to the irradiation-only group, the sucralfate-treated group exhibited smaller ulcer areas on the dorsal tongue, a greater number of basal layer cells in the dorsal tongue mucosa, significantly reduced levels of pro-apoptotic proteins Bax and Caspase-3, and significantly increased levels of the anti-apoptotic protein Bcl-2. Conclusion: Treatment with sucralfate improved the mucosal condition of the dorsal tongue in RIOM mice. It is hypothesized that sucralfate may alleviate local inflammation and promote mucosal healing through mechanisms such as forming a local barrier, promoting cell proliferation, inhibiting apoptosis, and scavenging free radicals.展开更多
SGLT-2抑制剂中芳基取代基是影响药物活性强弱的关键,本研究以恩格列净为先导化合物,对其芳基取代基进行修饰改造,设计合成4种新的SGLT-2抑制剂关键中间体,采用分子对接技术验证其设计合理性,经过酰氯化、亲电取代、亲核取代、还原四步...SGLT-2抑制剂中芳基取代基是影响药物活性强弱的关键,本研究以恩格列净为先导化合物,对其芳基取代基进行修饰改造,设计合成4种新的SGLT-2抑制剂关键中间体,采用分子对接技术验证其设计合理性,经过酰氯化、亲电取代、亲核取代、还原四步反应合成出产率最高可达90.2%的SGLT-2抑制剂关键中间体。最终结构均经1H-NMR、13C-NMR、HRMS联合验证。该路线具有操作简便、绿色高效、产率高的特点。为筛选出高活性SGLT-2抑制剂提供新思路。The aryl substituents in SGLT-2 inhibitors are the key factors affecting the strength of drug activity. In this study, empagliflozin was taken as the lead compound, and its aryl substituents were modified and transformed to design and synthesize four new key intermediates of SGLT-2 inhibitors. The rationality of the design was verified by molecular docking technology. The key intermediates of SGLT-2 inhibitors with a maximum yield of 90.2% were synthesized through four-step reactions including acyl chlorination, electrophilic substitution, nucleophilic substitution and reduction. The final structures were all jointly verified by 1H-NMR, 13C-NMR and HRMS. This synthetic route has the characteristics of simple operation, being environmentally friendly, highly efficient and having a high yield. It provides new ideas for screening out highly active SGLT-2 inhibitors.展开更多
醛酮还原酶家族1成员C3 (AKR1C3),也被称为5型17β羟基类固醇脱氢酶(17β-HSD5)或前列腺素F (PGF)合成酶,在雄激素生物合成中起关键作用。它催化弱雄激素、雌酮(弱雌激素)和PGD2分别转化为强雄激素(睾酮和5α-二氢睾酮)、17β-雌二醇(...醛酮还原酶家族1成员C3 (AKR1C3),也被称为5型17β羟基类固醇脱氢酶(17β-HSD5)或前列腺素F (PGF)合成酶,在雄激素生物合成中起关键作用。它催化弱雄激素、雌酮(弱雌激素)和PGD2分别转化为强雄激素(睾酮和5α-二氢睾酮)、17β-雌二醇(强雌激素)和11β-PGF2α。AKR1C3水平升高激活雄激素受体(AR) 8信号通路,促进肿瘤复发和对癌症治疗产生耐药性。AKR1C3的过表达作为一种致癌因子,促进癌细胞的增殖、侵袭和转移,并与癌症患者的不良预后和总生存期相关。抑制AKR1C3已被证明在抑制肿瘤进展和克服治疗耐药性方面具有强大的功效。因此,AKR1C3抑制剂的开发和设计引起了研究人员越来越多的兴趣,近年来取得了重大进展。本文简要介绍了AKR1C3的生理和病理功能,并对近年来选择性AKR1C3抑制剂的研究进展进行了综述。我们的目的是为未来的药物发现和潜在的治疗前景提供参考,新的、有效的、选择性的AKR1C3抑制剂。Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Here, we briefly review the physiological and pathological function of AKR1C3 and then summarize the recent development of selective AKR1C3 inhibitors. We aim to provide a reference for future drug discovery and potential therapeutic perspectives on novel, potent, selective AKR1C3 inhibitors.展开更多
目的:通过聚氨酯构建三维(3D)肺癌模型,并用于姜黄素药敏试验。方法:聚氨酯泡沫支架经I型胶原表面修饰后种植A549细胞构建肺癌3D模型,并进行姜黄素药敏试验。扫描电镜观察肺癌A549细胞生长情况。并均与2D培养下进行比较。结果:姜黄素可...目的:通过聚氨酯构建三维(3D)肺癌模型,并用于姜黄素药敏试验。方法:聚氨酯泡沫支架经I型胶原表面修饰后种植A549细胞构建肺癌3D模型,并进行姜黄素药敏试验。扫描电镜观察肺癌A549细胞生长情况。并均与2D培养下进行比较。结果:姜黄素可抑制A549的生长,浓度提高,抑制加强,呈剂量依赖性。3D培养条件下的细胞生长抑制率显著小于2D培养。结论:与2D培养相比,聚氨酯3D肺癌模型可能更好地模拟体内肺癌肿瘤微环境,提高临床前药物研究的预测能力,改善药物临床转化。Objective: To construct a three-dimensional (3D) lung cancer model by polyurethane and use it for curcumin drug sensitivity test. Methods: The 3D model of lung cancer was constructed by transplantation of A549 cells into polyurethane foam scaffolded with collagen type I surface modification, and curcumin susceptibility test was performed. The growth of lung cancer A549 cells was observed by scanning electron microscope. Then the results were compared with 2D culture. Results: Curcumin could inhibit the growth of A549. The concentration increased and the inhibition increased in a dose-dependent manner. The inhibition rate of 3D culture was significantly lower than that of 2D culture. Conclusion: Compared with 2D culture, polyurethane 3D lung cancer model may better simulate the microenvironment of lung cancer in vivo, and improve the predictive ability of preclinical drug studies, and improve the clinical transformation of drugs.展开更多
羟基红花黄色素A (Hydroxysafflor yellow A, HSYA)属于查尔酮苷类化合物质,具有广泛的药理作用和生理活性,如扩张冠状动脉、抗氧化、保护心肌、降血压、免疫抑制和脑保护等多种药理功能。对心血管系统具有保护作用,但因羟基红花黄色素...羟基红花黄色素A (Hydroxysafflor yellow A, HSYA)属于查尔酮苷类化合物质,具有广泛的药理作用和生理活性,如扩张冠状动脉、抗氧化、保护心肌、降血压、免疫抑制和脑保护等多种药理功能。对心血管系统具有保护作用,但因羟基红花黄色素A是水溶性查尔酮,跨膜能力差,不易吸收,所以对提高其生物利用度显得尤为重要,本文梳理羟基红花黄色素A对心脏的保护作用和提高其生物利用度研究的最新进展。Hydroxysafflor A (Hydroxysafflor yellow A, HSYA) belongs to chalcone glycoside compounds, with a wide range of pharmacological effects and physiological activities, such as coronary expansion, antioxidant, myocardial protection, blood pressure reduction, immune suppression and brain protection and other pharmacological functions. It has a protective effect on the cardiovascular system, but because hydroxyl safflower A is water-soluble chalcone, its transmembrane ability is poor, and it is not easy to absorb, so it is particularly important to improve its bioavailability. This paper reviews the latest progress of the protective effect of hydroxyl safflower A on the heart and improving its bioavailability.展开更多
为探索不同批次活性炭对参芪扶正稀释液中指标成分的吸附规律,本文首先建立了腺嘌呤、腺苷、毛蕊异黄酮苷、黄芪甲苷等四种指标成分含量的HPLC检测方法,并进行了方法学考察。结果表明腺嘌呤、腺苷、毛蕊异黄酮苷、黄芪甲苷分别在2.5~15 ...为探索不同批次活性炭对参芪扶正稀释液中指标成分的吸附规律,本文首先建立了腺嘌呤、腺苷、毛蕊异黄酮苷、黄芪甲苷等四种指标成分含量的HPLC检测方法,并进行了方法学考察。结果表明腺嘌呤、腺苷、毛蕊异黄酮苷、黄芪甲苷分别在2.5~15 µg/mL、5~30 µg/mL、5~30 µg/mL、0.1~0.8 mg/mL范围内线性关系良好。吸附动力学实验研究结果表明,不同批次活性炭吸附速率及平衡吸附量均存在较大差异。另外采用拟一级动力学和拟二级动力学对活性炭吸附过程进行建模,发现拟二级动力学能更好地拟合活性炭吸附过程。 To explore the adsorption law of different batches of activated carbon on the indicative constituents in the dilution of Shenqi Fuzheng Diluent, HPLC method for the detection of the content of four indicative constituents, including adenine, adenosine, calycosin 7-o-glucoside, and astragaloside A, was established, and the methodology was evaluated. The results showed that adenine, adenosine, calycosin 7-o-glucoside, and astragaloside A had a good linear relationship in the ranges of 2.5~15 μg/mL, 5~30 μg/mL, 5~30 μg/mL and 0.1~0.8 mg/mL, respectively. The results of adsorption kinetic experiments showed that there were great differences in the adsorption rate and equilibrium adsorption amount of different batches of activated carbon. In addition, the activated carbon adsorption process was modeled by pseudo-first-order kinetics and quasi-second-order kinetics, and it was found that the quasi-second-order kinetics could better fit the activated carbon adsorption process.展开更多
多糖作为生物体内普遍存在的生物大分子,其重要性不仅体现在作为生物体结构的基础成分上,更显著地展现在其具有抗病毒、抗菌、抗肿瘤和调节血糖等多样的生物活性上。众多研究成果表明天然多糖因其独特的生物活性,正逐步在药物研发领域...多糖作为生物体内普遍存在的生物大分子,其重要性不仅体现在作为生物体结构的基础成分上,更显著地展现在其具有抗病毒、抗菌、抗肿瘤和调节血糖等多样的生物活性上。众多研究成果表明天然多糖因其独特的生物活性,正逐步在药物研发领域展现其广泛的应用前景。本文对具有免疫增强潜力的天然多糖的生物资源来源、化学组成和结构特征进行综述,并对天然多糖在调节肠道菌群方面的理论基础研究进行总结的基础上探讨其免疫增强的作用机制,继而展望了这一领域的发展前景和方向。经过本文的深入探讨,我们旨在为天然多糖的免疫活性研究提供坚实的理论支撑,并期望能够激发研究者们对多糖免疫调节机制更深层次研究的全新思考。本文不仅对多糖在增强机体免疫力方面的潜在作用进行梳理,还揭示了其作为天然产物的独特优势,为未来的研究提供了新的方向。Polysaccharides, as ubiquitous biological macromolecules, play a crucial role not only as fundamental components of organism structures but also in various physiological activities such as antiviral, antibacterial, anti-tumor effects and blood glucose regulation. Extensive research has demonstrated that natural polysaccharides possess unique biological activities, gradually revealing their broad application prospects in drug research and development. In this review, we comprehensively summarize the biological resources, chemical composition, and structural characteristics of natural polysaccharides with immune-enhancing potential. Furthermore, we delve into the mechanisms underlying immune enhancement and focus on the theoretical basis of natural polysaccharides in regulating intestinal flora. Additionally, we prospectively discuss future directions for development in this field. The aim of this paper is to provide a solid theoretical foundation for studying the immune activity of natural polysaccharides while stimulating novel insights into the deeper understanding of their immune regulation mechanisms. This review not only summarizes the potential role of polysaccharides in enhancing immunity but also highlights their unique advantages as natural products—providing new avenues for future research.展开更多
目的:本研究旨在利用近红外光谱法建立一种快速检测正天丸素丸中水分含量的方法。方法:通过近红外光谱仪对正天丸素丸样品进行扫描,对光谱数据进行预处理和波段选择,并结合偏最小二乘法(partial least squares, PLS)建立了水分含量的快...目的:本研究旨在利用近红外光谱法建立一种快速检测正天丸素丸中水分含量的方法。方法:通过近红外光谱仪对正天丸素丸样品进行扫描,对光谱数据进行预处理和波段选择,并结合偏最小二乘法(partial least squares, PLS)建立了水分含量的快速无损检测模型。结果:研究显示,所建立的模型具有良好的性能,决定系数R达到0.97543,交叉验证均方根差值为0.64069。通过对验证集样品进行预测并进行统计分析,发现预测值与真实值之间无显著差异(P > 0.05)。结论:所建立的模型具有高准确度,适用于正天丸素丸中水分的快速检测,为相关领域提供了一种可行的分析方法。展开更多
文摘JAK抑制剂因能够抑制JAK/STAT信号通路从而治疗炎症和自身免疫疾病,逐渐成为药物研究领域的热点,但面对庞大的潜在药物分子如何有效地筛选从而得到有效的药物分子仍然面临着挑战。因此通过计算机辅助处理分子信息,并结合分子对接、药代动力学、分子动力学、机器学习等相关技术进行药物分子的虚拟筛选从而为接下来的药物合成,生物测试等提供重要的研究思路,本文主要综述使用计算机辅助药物设计技术在JAK小分子抑制剂研究中的相关进展,介绍其相关的设计思路,并对计算机辅助药物设计的发展前景做出展望。JAK inhibitors, which can suppress the JAK/STAT signaling pathway to treat inflammatory and autoimmune diseases, have gradually become a hot topic in the field of drug research. However, faced with a vast number of potential drug molecules, effectively screening to obtain effective drug molecules still poses a significant challenge. Therefore, by using computer-aided processing of molecular information, combined with related technologies such as molecular docking, pharmacokinetics, molecular dynamics, and machine learning, to conduct virtual screening of drug molecules, important research ideas are provided for subsequent drug synthesis and biological testing. This article mainly reviews the advancements in the research of JAK small molecule inhibitors using computer-aided drug design techniques, introduces the related design concepts, and offers a perspective on the future development of computer-aided drug design.
文摘目的:将微管蛋白抑制剂康普瑞汀(Combretastatin A4, CA4)的顺式二苯乙烯结构改造为偶氮苯类化合物,以其体内分布的特异性活化性能来增强其靶向性。方法:以3,4,5-三甲氧基苯胺为起始原料,经过重氮化反应后,与邻炔丙氧基苯酚进行偶合,得到关键中间体AzO-OH;关键中间体进一步与碘甲烷、溴丙烷或溴代正丁烷在K2CO3存在下进行酚羟基的取代反应,得到产物AzO-Me,AzO-Pr,AzO-Bu。结果:设计并合成得到CA4的偶氮化衍生物,其结构经NMR、MS确证;分子对接表明,该类化合物与微管蛋白具有较强的结合性,其结合模式与顺式CA4相近,因而可能具有类似或更强的微管蛋白抑制作用;光学性能研究发现,该类偶氮化合物在不同波长光照下会发生顺-反或反-顺的构型变化;初步的药理实验的结果显示,细胞增殖抑制活性在光照后大大提高。结论:将CA4改造为偶氮苯类化合物后,通常情况下以无生物活性但性质更稳定的反式结构存在,而在体内靶部位给予特定波段的光,就可以转化为具有活性的顺式结构发挥作用,从而可以实现“全身给药,局部激活”的靶向性能,加强了CA4的靶向性,初步的药理实验证实了上述设想。Objective: To transform the cis-stilbene structure of the tubulin inhibitor Combretastatin A4 (CA4) into an azobenzene compound, so as to enhance its targeting ability in vivo. Method: The starting material 3,4,5-trimethoxyaniline was diazotized, then coupling with o-propargyloxyphenol to obtain the key intermediate AzO-OH;the key intermediate was further substituted with the reaction of the phenolic hydroxyl group to obtain the product AzO-Me, AzO-Pr, AzO-Bu, by combining with methyl iodide, bromopropane or bromo-n-butane in the presence of K2CO3. Results: The azo derivatives of CA4 were synthesized. Their structures were confirmed by NMR and MS. Molecular docking showed that these compounds had strong binding activities to tubulin, and the binding modes were similar to that of cis-CA4. So they may have a similar or stronger inhibitory effect on tubulin. Optical performance studies have found that this type of azo compound undergoes a cis to trans or trans to cis configuration changes under different wavelengths of light. The results of preliminary pharmacological experiments showed that the inhibitory activity of cell proliferation was greatly improved after illumination. Conclusions: After transforming CA4 into azobenzene compound, it usually exists as a stable trans-structure with no or little biological activity. However, given a specific wavelength of light at the target site in the body, it can be converted into an active cis-form. The structure plays an important role, so that the targeting performance of “systemic administration, local activation” can be realized, and the targeting ability of CA4 can be enhanced. Preliminary pharmacological experiments confirmed the hypothesis.
文摘本研究以胶凝时间为评价指标,通过单因素试验法考察了连翘温敏口腔凝胶中泊洛沙姆407 (F127)、泊洛沙姆188 (F68)和丙三醇的配比对胶凝时间的影响,以响应面法优化了该凝胶的制备工艺。采用目测法观察连翘温敏口腔凝胶的性状和外观,pH试纸测定其pH值,恒温水浴中测定胶凝时间和胶凝温度,采用透析袋法,以PBS缓冲液为释放基质,考察了该凝胶的体外释药性能。结果表明,连翘温敏口腔凝胶的最优配比为F127含量17%、F68含量6%、丙三醇含量4%。该连翘温敏口腔凝胶为橘黄色均一透明具凝胶特性的稠厚液体,pH值为6.5~6.8,均一性良好,胶凝温度为35 ± 0.2℃,胶凝时间为10.5 ± 0.1 s。体外释放试验结果表明该凝胶在释放介质中展现出了良好的缓释性能。In this study, forsythia thermosensitive oral gel was prepared and the preparation process was optimized. Single factor experiment was conducted to explore the influence of the ratio of Poloxam 407 (F127), Poloxam 188 (F68), and glycerol in forsythia thermosensitive oral gel on the gel time, and response surface method was used to optimize the preparation process of the gel. The characteristics and appearance of forsythia thermosensitive oral gels were observed by visual method, pH values were determined by pH test paper, gel time and gel temperature were determined in a constant temperature water bath. The in vitro release performance of forsythoside A in the gels was investigated by the dialysis bag method with PBS buffer used as the release medium. According to the analysis of the overall experimental study, the optimal proportions of the gels were obtained as follows: the ratio of Poloxham 407 was 17%, Poloxham 188 was 6% and glycerol was 4%. The prepared forsythia thermosensitive oral gel was orange, transparent and gel thick liquid, pH value was 6.5~6.8, the uniformity is good, gel temperature was 35 ± 0.2˚C, and gel time was 10.5 ± 0.1 s. In vitro release experiments results showed that the prepared gels exhibited good sustained-release performance in the provided release medium.
文摘[目的]本研究基于网络药理学与分子对接技术,系统探讨三叶青对动脉粥样硬化的潜在抗病机制,明确其主要有效成分、作用靶点及相关信号通路,为三叶青的药理作用研究提供理论依据。[方法]通过TCMSP数据库并结合特定筛选条件,确定三叶青的主要有效成分及其对应的靶点,并构建“有效成分–靶点网络”。进一步利用GeneCards和OMIM数据库筛选与动脉粥样硬化相关的疾病靶点,从中获取药物靶点与疾病靶点的交集。在此基础上,对交集靶点进行蛋白质互作(PPI)网络分析、基因本体(GO)生物功能富集分析和KEGG信号通路富集分析。同时应用Cytoscape 3.7.2软件中的“Analyze Network”工具,构建“有效成分–靶点–通路”网络。最后,通过分子对接方法验证关键有效成分与核心靶点之间的亲和力。[结果]筛选出三叶青的9种主要有效成分,其中7种成分与靶点具有明确的对应关系,而2种因药代动力学而舍弃。通过分析获得2084个与动脉粥样硬化相关的疾病靶点,并筛选出77个药物靶点与疾病靶点的交集。PPI网络分析显示,AKT1、PPARG、PTGS2、EGFR和ESR1等是主要的核心靶点。GO生物功能富集分析中,共获得285个与生物过程相关的条目、44个与细胞成分相关的条目以及108个与分子功能相关的条目。KEGG信号通路富集分析筛选出108条显著富集的信号通路,主要涉及内分泌抵抗、EGFR酪氨酸激酶抑制剂耐药性以及花生四烯酸代谢等关键通路。分子对接结果显示,槲皮素、山柰素、异鼠李素和山奈酚与AKT1靶点具有较高的结合亲和力,表明这些成分可能是三叶青发挥药理作用的核心成分。[结论]研究结果表明,三叶青中的核心有效成分槲皮素、山柰素、异鼠李素和山奈酚可能通过调控脂质代谢与动脉粥样硬化相关的关键信号通路,作用于核心靶点AKT1,从而在蛋白质结合、酶结合及可识别蛋白结合等生物学功能中发挥抗动脉粥样硬化的作用。本研究为三叶青的进一步开发和利用提供了理论支持。Aim: This study systematically investigates the potential anti-atherosclerotic mechanisms of Tetrastigma hemsleyanum (San Ye Qing) using network pharmacology and molecular docking approaches. It aims to identify the primary active components, potential targets, and associated signaling pathways, providing a theoretical foundation for the pharmacological research of Tetrastigma hemsleyanum. Methods: The main active components of Tetrastigma hemsleyanum and their corresponding targets were identified through the TCMSP database with specific screening criteria, and the “active component-target network” was constructed. Subsequently, disease targets related to atherosclerosis were retrieved from the GeneCards and OMIM databases, and the intersection of drug targets and disease targets was obtained. Protein-protein interaction (PPI) network analysis, Gene Ontology (GO) biological function enrichment analysis, and KEGG pathway enrichment analysis were performed on the intersected targets. The “active component-target-pathway network” was constructed using the Analyze Network tool in Cytoscape 3.7.2. Finally, molecular docking was employed to verify the binding affinity between key active components and core targets. Results: Nine major active components of Tetrastigma hemsleyanum were identified, seven of which had clear corresponding targets, while two were excluded due to poor pharmacokinetic properties. A total of 2084 disease-related targets for atherosclerosis were obtained, with 77 overlapping targets identified as the intersection of drug and disease targets. PPI network analysis revealed that AKT1, PPARG, PTGS2, EGFR, and ESR1 were the primary core targets. GO enrichment analysis identified 285 biological process terms, 44 cellular component terms, and 108 molecular function terms. KEGG pathway enrichment analysis revealed 108 significantly enriched signaling pathways, primarily involving endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and arachidonic acid metabolism. Molecular docking demonstrated that quercetin, kaempferol, isorhamnetin, and kaempferide exhibited strong binding affinities to the core target AKT1, suggesting that these components may be the key active ingredients of Tetrastigma hemsleyanum. Conclusion: The results suggest that the core active components of quercetin, kaempferol, isorhamnetin, and kaempferide in Tetrastigma hemsleyanum may exert anti-atherosclerotic effects by regulating key signaling pathways related to lipid metabolism and atherosclerosis, such as the MAPK signaling pathway. These components likely act on the core target AKT1 to mediate biological functions such as protein binding, enzyme binding, and protein recognition. This study provides a theoretical basis for the further development and utilization of Tetrastigma hemsleyanum.
文摘本文借助密度泛函理论中的B3LYP算法,基于6-31G(d)理论基组,深入探讨了甲氧氯普胺分子的结构特性,成功获取了其稳定的分子构象及红外光谱属性。研究揭示,甲氧氯普胺的红外振动光谱因振动模式的差异,主要分布于三个频率范围:低频段(0~500) cm−1、中频段(500~2000) cm−1和高频段(2000~4000) cm−1。此外,由于简并振动及非红外活性振动的存在,实际红外光谱中可辨识的谱线少于理论预测的简正振动数目。In this paper, the B3LYP algorithm within Density Functional Theory (DFT), based on the 6-31G(d) theoretical basis set, is employed to delve into the structural characteristics of the metoclopramide molecule. Stable molecular conformations and infrared spectral properties of metoclopramide are successfully obtained. The study reveals that the infrared vibrational spectrum of metoclopramide is mainly distributed across three frequency ranges due to different vibrational modes: the low-frequency range (0~500) cm−1, the mid-frequency range (500~2000) cm−1, and the high-frequency range (2000~4000) cm−1. Additionally, due to the presence of degenerate vibrations and non-infrared-active vibrations, the number of identifiable spectral lines in the actual infrared spectrum is less than the number of normal vibrations theoretically predicted.
文摘本文详述了一项针对二肽基肽酶4 (DPP4)靶点的创新药物研发策略,该策略通过整合虚拟筛选、分子对接与分子动力学模拟三大前沿技术,实现了药物研发效率与精度的双重提升。研究从大型化合物库出发,运用先进算法与机器学习工具高效筛选出与DPP4靶点具有潜在高结合亲和力的候选分子,大幅缩减实验候选范围。随后,采用分子对接技术深入剖析候选分子与靶点的相互作用模式、能量特征及关键氨基酸残基的作用机制,成功筛选出高亲和力、高选择性的先导化合物。为进一步验证与优化,研究引入分子动力学模拟,动态观测候选药物在生物环境中的构象稳定性、溶剂化效应及与靶点的动态结合,为药物设计提供了科学依据,加速了DPP4抑制剂的研发进程,为糖尿病及其他代谢性疾病的治疗开辟了新前景。This paper details an innovative drug development strategy targeting dipeptidyl peptidase-4 (DPP4), which integrates three cutting-edge technologies: virtual screening, molecular docking, and molecular dynamics simulations. This strategy enhances both the efficiency and accuracy of drug development. The study begins with a large compound library, employing advanced algorithms and machine learning tools to efficiently screen for candidate molecules with potential high binding affinity to the DPP4 target, significantly narrowing down the pool of experimental candidates. Subsequently, molecular docking techniques are used to deeply analyze the interaction patterns, energy characteristics, and the role of key amino acid residues between the candidate molecules and the target, successfully identifying lead compounds with high affinity and selectivity. To further validate and optimize, the study incorporates molecular dynamics simulations to dynamically observe the conformational stability, solvation effects, and dynamic binding with the target in a biological environment. This provides scientific evidence for drug design, accelerates the development of DPP4 inhibitors, and opens new prospects for the treatment of diabetes and other metabolic diseases.
文摘在过去的二十年里,随着IMiD和indisulam等MG降解剂的出现,分子胶(MGs)逐渐引起了制药界的关注。这些分子通过促进靶蛋白和E3连接酶之间的相互作用来降解靶蛋白。此外,MGs作为化学诱导剂,促进同源蛋白和异源蛋白的二聚化形成三元复合物,在调节生物活性方面具有很大的前景。本文重点介绍MGs在药物开发领域的应用,包括蛋白质–蛋白质相互作用(PPI)稳定性和蛋白质降解。我们深入分析了各种MGs的结构以及MGs与各种生物活性分子之间的相互作用,从而为PPI稳定剂和新型降解剂的开发提供了新的视角。Over the past two decades, molecular glues (MGs) have gradually attracted the attention of the pharmaceutical community with the advent of MG degraders such as IMiDs and indisulam. Such molecules degrade the target protein by promoting the interaction between the target protein and E3 ligase. In addition, as a chemical inducer, MGs promote the dimerization of homologous proteins and heterologous proteins to form ternary complexes, which have great prospects in regulating biological activities. This review focuses on the application of MGs in the field of drug development including protein-protein interaction (PPI) stability and protein degradation. We thoroughly analyze the structure of various MGs and the interactions between MGs and various biologically active molecules, thus providing new perspectives for the development of PPI stabilizers and new degraders.
文摘目的:探索硫糖铝对小鼠放射性口腔黏膜炎(radiation-induced oral mucositis;RIOM)的治疗效果及其可能机制。材料和方法:建立小鼠RIOM模型,从小鼠辐照完成后至处死小鼠期间,每日使用硫糖铝局部涂抹小鼠舌背,观察溃疡情况,并行组织病理学和WB检测。结果:18 Gy γ射线大剂量一次性照射头颈部后第9天小鼠舌部出现明显的溃疡。与单纯辐照组相比,硫糖铝处理组小鼠舌背溃疡面积较小,舌背黏膜基底层细胞更多,组织内促凋亡蛋白Bax和Caspase-3水平显著降低,抗凋亡蛋白Bcl-2水平显著升高。结论:使用硫糖铝治疗能改善RIOM小鼠的舌背黏膜情况,推测可能是通过形成局部屏障、促进细胞增殖、抗细胞凋亡、清除自由基等方面作用从而减轻口腔黏膜局部炎症,促进黏膜炎愈合。Purpose: To investigate the therapeutic effects of sucralfate on radiation-induced oral mucositis (RIOM) in mice and explore its potential mechanisms. Materials and Methods: A mouse model of RIOM was established. From the completion of irradiation until euthanasia, sucralfate was topically applied to the dorsal tongue of mice daily. Ulcer conditions were observed, and histopathological and Western blot (WB) analyses were performed. Results: On the 9th day after a single high-dose (18 Gy) γ-ray irradiation of the head and neck, significant ulcers appeared on the tongues of mice. Compared to the irradiation-only group, the sucralfate-treated group exhibited smaller ulcer areas on the dorsal tongue, a greater number of basal layer cells in the dorsal tongue mucosa, significantly reduced levels of pro-apoptotic proteins Bax and Caspase-3, and significantly increased levels of the anti-apoptotic protein Bcl-2. Conclusion: Treatment with sucralfate improved the mucosal condition of the dorsal tongue in RIOM mice. It is hypothesized that sucralfate may alleviate local inflammation and promote mucosal healing through mechanisms such as forming a local barrier, promoting cell proliferation, inhibiting apoptosis, and scavenging free radicals.
文摘SGLT-2抑制剂中芳基取代基是影响药物活性强弱的关键,本研究以恩格列净为先导化合物,对其芳基取代基进行修饰改造,设计合成4种新的SGLT-2抑制剂关键中间体,采用分子对接技术验证其设计合理性,经过酰氯化、亲电取代、亲核取代、还原四步反应合成出产率最高可达90.2%的SGLT-2抑制剂关键中间体。最终结构均经1H-NMR、13C-NMR、HRMS联合验证。该路线具有操作简便、绿色高效、产率高的特点。为筛选出高活性SGLT-2抑制剂提供新思路。The aryl substituents in SGLT-2 inhibitors are the key factors affecting the strength of drug activity. In this study, empagliflozin was taken as the lead compound, and its aryl substituents were modified and transformed to design and synthesize four new key intermediates of SGLT-2 inhibitors. The rationality of the design was verified by molecular docking technology. The key intermediates of SGLT-2 inhibitors with a maximum yield of 90.2% were synthesized through four-step reactions including acyl chlorination, electrophilic substitution, nucleophilic substitution and reduction. The final structures were all jointly verified by 1H-NMR, 13C-NMR and HRMS. This synthetic route has the characteristics of simple operation, being environmentally friendly, highly efficient and having a high yield. It provides new ideas for screening out highly active SGLT-2 inhibitors.
文摘醛酮还原酶家族1成员C3 (AKR1C3),也被称为5型17β羟基类固醇脱氢酶(17β-HSD5)或前列腺素F (PGF)合成酶,在雄激素生物合成中起关键作用。它催化弱雄激素、雌酮(弱雌激素)和PGD2分别转化为强雄激素(睾酮和5α-二氢睾酮)、17β-雌二醇(强雌激素)和11β-PGF2α。AKR1C3水平升高激活雄激素受体(AR) 8信号通路,促进肿瘤复发和对癌症治疗产生耐药性。AKR1C3的过表达作为一种致癌因子,促进癌细胞的增殖、侵袭和转移,并与癌症患者的不良预后和总生存期相关。抑制AKR1C3已被证明在抑制肿瘤进展和克服治疗耐药性方面具有强大的功效。因此,AKR1C3抑制剂的开发和设计引起了研究人员越来越多的兴趣,近年来取得了重大进展。本文简要介绍了AKR1C3的生理和病理功能,并对近年来选择性AKR1C3抑制剂的研究进展进行了综述。我们的目的是为未来的药物发现和潜在的治疗前景提供参考,新的、有效的、选择性的AKR1C3抑制剂。Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Here, we briefly review the physiological and pathological function of AKR1C3 and then summarize the recent development of selective AKR1C3 inhibitors. We aim to provide a reference for future drug discovery and potential therapeutic perspectives on novel, potent, selective AKR1C3 inhibitors.
文摘目的:通过聚氨酯构建三维(3D)肺癌模型,并用于姜黄素药敏试验。方法:聚氨酯泡沫支架经I型胶原表面修饰后种植A549细胞构建肺癌3D模型,并进行姜黄素药敏试验。扫描电镜观察肺癌A549细胞生长情况。并均与2D培养下进行比较。结果:姜黄素可抑制A549的生长,浓度提高,抑制加强,呈剂量依赖性。3D培养条件下的细胞生长抑制率显著小于2D培养。结论:与2D培养相比,聚氨酯3D肺癌模型可能更好地模拟体内肺癌肿瘤微环境,提高临床前药物研究的预测能力,改善药物临床转化。Objective: To construct a three-dimensional (3D) lung cancer model by polyurethane and use it for curcumin drug sensitivity test. Methods: The 3D model of lung cancer was constructed by transplantation of A549 cells into polyurethane foam scaffolded with collagen type I surface modification, and curcumin susceptibility test was performed. The growth of lung cancer A549 cells was observed by scanning electron microscope. Then the results were compared with 2D culture. Results: Curcumin could inhibit the growth of A549. The concentration increased and the inhibition increased in a dose-dependent manner. The inhibition rate of 3D culture was significantly lower than that of 2D culture. Conclusion: Compared with 2D culture, polyurethane 3D lung cancer model may better simulate the microenvironment of lung cancer in vivo, and improve the predictive ability of preclinical drug studies, and improve the clinical transformation of drugs.
文摘羟基红花黄色素A (Hydroxysafflor yellow A, HSYA)属于查尔酮苷类化合物质,具有广泛的药理作用和生理活性,如扩张冠状动脉、抗氧化、保护心肌、降血压、免疫抑制和脑保护等多种药理功能。对心血管系统具有保护作用,但因羟基红花黄色素A是水溶性查尔酮,跨膜能力差,不易吸收,所以对提高其生物利用度显得尤为重要,本文梳理羟基红花黄色素A对心脏的保护作用和提高其生物利用度研究的最新进展。Hydroxysafflor A (Hydroxysafflor yellow A, HSYA) belongs to chalcone glycoside compounds, with a wide range of pharmacological effects and physiological activities, such as coronary expansion, antioxidant, myocardial protection, blood pressure reduction, immune suppression and brain protection and other pharmacological functions. It has a protective effect on the cardiovascular system, but because hydroxyl safflower A is water-soluble chalcone, its transmembrane ability is poor, and it is not easy to absorb, so it is particularly important to improve its bioavailability. This paper reviews the latest progress of the protective effect of hydroxyl safflower A on the heart and improving its bioavailability.
文摘为探索不同批次活性炭对参芪扶正稀释液中指标成分的吸附规律,本文首先建立了腺嘌呤、腺苷、毛蕊异黄酮苷、黄芪甲苷等四种指标成分含量的HPLC检测方法,并进行了方法学考察。结果表明腺嘌呤、腺苷、毛蕊异黄酮苷、黄芪甲苷分别在2.5~15 µg/mL、5~30 µg/mL、5~30 µg/mL、0.1~0.8 mg/mL范围内线性关系良好。吸附动力学实验研究结果表明,不同批次活性炭吸附速率及平衡吸附量均存在较大差异。另外采用拟一级动力学和拟二级动力学对活性炭吸附过程进行建模,发现拟二级动力学能更好地拟合活性炭吸附过程。 To explore the adsorption law of different batches of activated carbon on the indicative constituents in the dilution of Shenqi Fuzheng Diluent, HPLC method for the detection of the content of four indicative constituents, including adenine, adenosine, calycosin 7-o-glucoside, and astragaloside A, was established, and the methodology was evaluated. The results showed that adenine, adenosine, calycosin 7-o-glucoside, and astragaloside A had a good linear relationship in the ranges of 2.5~15 μg/mL, 5~30 μg/mL, 5~30 μg/mL and 0.1~0.8 mg/mL, respectively. The results of adsorption kinetic experiments showed that there were great differences in the adsorption rate and equilibrium adsorption amount of different batches of activated carbon. In addition, the activated carbon adsorption process was modeled by pseudo-first-order kinetics and quasi-second-order kinetics, and it was found that the quasi-second-order kinetics could better fit the activated carbon adsorption process.
文摘多糖作为生物体内普遍存在的生物大分子,其重要性不仅体现在作为生物体结构的基础成分上,更显著地展现在其具有抗病毒、抗菌、抗肿瘤和调节血糖等多样的生物活性上。众多研究成果表明天然多糖因其独特的生物活性,正逐步在药物研发领域展现其广泛的应用前景。本文对具有免疫增强潜力的天然多糖的生物资源来源、化学组成和结构特征进行综述,并对天然多糖在调节肠道菌群方面的理论基础研究进行总结的基础上探讨其免疫增强的作用机制,继而展望了这一领域的发展前景和方向。经过本文的深入探讨,我们旨在为天然多糖的免疫活性研究提供坚实的理论支撑,并期望能够激发研究者们对多糖免疫调节机制更深层次研究的全新思考。本文不仅对多糖在增强机体免疫力方面的潜在作用进行梳理,还揭示了其作为天然产物的独特优势,为未来的研究提供了新的方向。Polysaccharides, as ubiquitous biological macromolecules, play a crucial role not only as fundamental components of organism structures but also in various physiological activities such as antiviral, antibacterial, anti-tumor effects and blood glucose regulation. Extensive research has demonstrated that natural polysaccharides possess unique biological activities, gradually revealing their broad application prospects in drug research and development. In this review, we comprehensively summarize the biological resources, chemical composition, and structural characteristics of natural polysaccharides with immune-enhancing potential. Furthermore, we delve into the mechanisms underlying immune enhancement and focus on the theoretical basis of natural polysaccharides in regulating intestinal flora. Additionally, we prospectively discuss future directions for development in this field. The aim of this paper is to provide a solid theoretical foundation for studying the immune activity of natural polysaccharides while stimulating novel insights into the deeper understanding of their immune regulation mechanisms. This review not only summarizes the potential role of polysaccharides in enhancing immunity but also highlights their unique advantages as natural products—providing new avenues for future research.
