小檗碱衍生物9-OH小檗碱的抗帕金森病活性和作用机制研究

目的: 探究小檗碱衍生物9-OH小檗碱对1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride,MPTP)诱导的斑马鱼帕金森病(Parkinson’s disease,PD)症状是否具有缓解作用。方法: 受精后1 d (day post fertilization,dpf)的斑马鱼胚胎,设置空白对照组,50 μmol·L^-1 MPTP造模组,50 μmol·L^-1 MPTP与不同质量浓度(100,300,500 μmol·L^-1)9-OH小檗碱共处理组。4 dpf时,分别观察并记录各组斑马鱼多巴胺神经元及脑部血管的发育情况;5 dpf时,监测行为学,记录各组行为学数据并分析差异,收集后检测PD相关基因表达变化,包括编码α-突触核蛋白(α-synuclein,α-Syn)的α-syn、编码E3泛素连接酶(E3 ubiquitin protein ligase,Parkin)的parkin、编码自噬相关基因5(autophagy related gene 5,Atg5)的atg5、编码微管相关蛋白1轻链3B (microtubule-associated protein 1 light chain 3B,Lc3b)的lc3b。结果: MPTP造模组的斑马鱼多巴胺神经元和脑部血管出现不同程度的损伤,且出现运动迟缓、焦虑等PD状行为,与PD相关的基因表达也出现异常;而MPTP与9-OH小檗碱共处理组的斑马鱼多巴胺神经元和脑部血管的损伤得到改善,行为学能力得到恢复,且PD相关基因的表达趋于正常。结论: 小檗碱衍生物9-OH小檗碱对MPTP诱导的斑马鱼帕金森病症状有缓解作用。     

小檗碱衍生物的活性研究进展

小檗碱是一种来源于植物的天然药物,其在医药领域内具有广泛的应用价值。本文综述了近年来小檗碱衍生物的活性研究进展,旨在能为以天然产物小檗碱为核心的结构改造上提供一些有益的帮助。     

小檗碱及其衍生物的抗肥胖作用

肥胖是长期能量摄入与消耗不平衡而引起的一种慢性代谢性疾病,与脂肪组织的异常增殖与肥大密切相关,抑制前脂肪细胞的增殖和分化也是抑制肥胖的一种方法。近些年,小檗碱(BBR)被发现具有抑制脂肪细胞增殖分化和脂质积累的能力,并通过PI3K-AKT、Ucp1、AMPK、AMPK-PGC1α轴影响脂肪细胞分化的进程。本篇综述介绍了BBR对脂肪细胞增殖分化、脂质积累和脂肪产热的影响,从而为BBR如何通过脂肪产热帮助预防和管理肥胖的干预策略提供新的见解。     

小檗碱抗炎活性研究

目的观察小檗碱的抗炎作用。方法采用甲醛致小鼠足肿胀法观察小檗碱对炎症局部组织中前列腺素(PGE2)的影响。结果小檗碱能显著降低炎性组织中PGE2的含量。结论小檗碱具有明显抗炎作用,其机制与抑制组织中PGE2生成有关。     

小檗碱衍生物的合成及其抗血管生成活性研究

目的结构拼合是获得先导化合物的有效途径,以此为指导合成一系列新型小檗碱衍生物,并用Ⅳ型胶原酶和鸡胚尿囊膜(CAM)模型评价其活性和安全性。方法以小檗碱为母核,结合中药常见活性成分,运用"拼合原理",设计、合成小檗碱系列衍生物,并采用课题组前期建立的Ⅳ型胶原酶和CAM模型,快速评价小檗碱衍生物对Ⅳ型胶原酶的抑制作用和对新生胚胎血管生成的影响。结果设计并合成了4个新化合物,结构经1H-NMR、13C-NMR和HRMS确认,其中化合物CYQ-44、CYQ-48、CYQ-50对Ⅳ型胶原酶有剂量相关性抑制作用,且均高于阳性药盐酸四环素;与此同时,化合物CYQ-48、CYQ-对新生胚胎血管生成有一定抑制作用。结论成功合成了4个新型小檗碱衍生物,它们不仅对Ⅳ型胶原酶和新生血管具有抑制作用,而且安全指数高,进一步表明以结构拼合为指导可高效、简便获得具有中医药特点的先导化合物。     

四氢小檗碱衍生物的合成及活性研究现状

四氢小檗碱为季铵型异喹啉类生物碱小檗碱的还原产物,具有抗菌、降糖、降血脂、抗心律失常等多种活性.同时四氢小檗碱不稳定,存在口服生物利用率低,靶向性不强等缺点,因此,针对四氢小檗碱进行结构改造的研究也越来越多.近年来四氢小檗碱的改造主要集中在9位、12位以及7位氮原子上,本文对四氢小檗碱及其衍生物的合成和活性研究进行综述...     

小檗碱及其衍生物的研究进展

小檗碱是从中草药黄连等植物中提取分离得到的一类异喹啉类生物碱。近十年来，已经有2 000多篇国内外文献报道了小檗碱及其衍生物在治疗肿瘤、糖尿病、心血管疾病、高血脂、炎症、细菌和病毒感染、脑缺血性损伤、精神疾病、阿尔茨海默病(Alzheimer disease)、骨质疏松等多方面的临床应用、药效机制以及该类化合物的构效关系等研究结果。这些结果表明小檗碱生理功能广泛，潜在的结构改造和开发应用价值很大，但还未见系统的回顾和综述。本文对这些文献进行了系统地分析整理，主要从临床应用与药效机制、分子药理、体内吸收代谢、构效关系四个方面来介绍小檗碱及其衍生物的研究进展，旨在为进一步深入开展以药效机制为基础的小檗碱结构改造和创新药物研究提供比较系统的信息。     

小檗碱抑制结肠癌细胞中COX-2表达作用的研究

目的:研究小檗碱(Ber)抑制肿瘤细胞中环氧合酶-2(COX-2)表达与时间及浓度的关系,探讨Ber作为抗肿瘤药物的可能.方法:以结肠癌细胞系HT-29为研究对象,培养后加入不同浓度的Ber,用荧光定量PCR法观察其对COX-2的抑制作用,MTT法检测Ber对癌细胞的杀伤作用.结果:在浓度大于0.25μmol·L-1时Ber对COX-2有抑制作用,与时间、浓度正相关.在浓度大于3.0μmol·L-1时对癌细胞有杀伤作用.结论:Ber可抑制COX-2及癌细胞生长,推测Ber有一定的抑癌作用,可望成为一种新型的抗癌药.     

小檗碱抗兔动脉粥样硬化的实验研究

目的评价小檗碱（BBR）对预防家兔动脉粥样硬化发生及斑块破裂、血栓形成疗效,并探讨其可能的作用机制。方法选用新西兰大白兔40只,采用球囊损伤＋高脂饮食＋药物触发综合的方法建立动脉粥样硬化模型。随机分4组：普通饲料喂养、单纯球囊损伤＋高脂、球囊损伤＋高脂＋小檗碱干预和球囊损伤＋高脂1＋辛伐他汀干预。检测不同时期血脂水平及药物触发前血清ox-LDL、Lp—PLA2、MCP-1、MMP-9、TIMP-1水平。观察斑块破裂和血栓形成情况;并苏木素一伊红（HE）染色,利用微机图像处理测量系统对切片进行图像摄取和转换,测量病变内、中膜的厚度。结果小檗碱可显著降低高脂饮食兔血清TC、TG、LDL-C水平,显著降低血清ox-LDL、Lp-PLA2、MCP-1、MMP-9水平,升高血清TIMP-1水平,与他汀干预组无显著差异。小檗碱组弹力纤维破坏不明显,仍呈连续排列,内膜也有局限性轻度增厚,中膜变薄,内膜厚度小于中膜厚度。小檗碱组的内膜增生程度小于阳性对照组,中膜也没有阳性对照组萎缩明显,和辛伐他汀组的内膜增生程度和中膜萎缩程度近似,药物激发无一例发生斑块破裂与血栓形成。结论小檗碱可显著改善AS病变程度及稳定斑块,作用效果与辛伐他汀相似,其机制可能与小檗碱能显著降低血清及血清各炎症标志物水平等作用有关。     

取代环戊酮曼尼希碱的合成及其抗炎活性

目的 对环戊酮曼尼希碱类化合物JC9118进行结构改造，设计合成其类似物并初步评价抗炎活性。方法 以N－环戊烯基吗啉，对异丁基苯甲醛，对异丁基苯乙酮及多种胺类为原料经Stork反应，Mannich反应和胺交换反应合成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果 合成9个新化合物，经IR，^1H-NMR和MS确证其结构；其中5个化合物具有显著的抗炎活性。结论 JC9118的芳胺曼尼希碱类似物无抗炎活性；羰基α位的取代亚苄基对保持化合物的抗炎活性起重要作用。     

Pharmacological effects of berberine and its derivatives: a patent update

Introduction: A number of plant-derived agents are used in many therapeutic areas. Berberine, an important protoberberine alkaloid, is present in a number of medicinal plants that have been widely used in traditional Chinese medicine for hundreds of years. Modern research has shown that berberine and its derivatives display several pharmacological effects through various mechanisms.

Areas covered: This review discusses recent and mostly Chinese patents that report the synthesis of berberine, berberine derivatives and berberine salts, and methods of preparation for formulations (traditional Chinese medicine) containing herbal components rich in berberine, along with their applications. The review covers several therapeutic effects of berberine, its derivatives and pharmaceutical formulations against cancer, obesity, diabetes, inflammation, atherosclerosis, Alzheimer’s disease, rheumatoid arthritis and cardiovascular diseases. In addition, the mechanisms underlying the pharmacological effects are discussed.

Expert opinion: Modification of the functional groups of berberine has a significant effect on the pharmacological activity. However, studies on altering the atoms and size of the berberine skeleton are rare. Thus, it may be beneficial to initiate a drug development program focused on inserting heterocyclic rings of different sizes into berberine. Furthermore, structural modification to improve the safety, efficacy and selectivity is necessary to promote the use of berberine-based drugs in clinical settings.     

In vitro antioxidant and anti-cholinesterase activities of Rhizophora mucronata

Context: Rhizophora mucronata Lam. (Rhizophoraceae), commonly known as Asiatic mangrove, has been used traditionally among Asian countries as folk medicine.

Objective: This study investigates the cholinesterase inhibitory potential and antioxidant activities of R. mucronata.

Materials and method: Rhizophora mucronata leaves were successively extracted using solvents of varying polarity and a dosage of 100–500?µg/ml were used for each assay. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were assessed according to the method of Ellman. In vitro antioxidant activity was assessed using free radical scavenging, reducing power, and metal-chelating activity (duration – 3 months). Total phenolic and flavonoid content were quantified spectrophotometrically. Compound characterization was done using column chromatography, NMR, FTIR, and LC-MS analysis.

Results: Methanolic leaf extract (500?µg/ml) exhibited the highest inhibitory activity against AChE (92.73?±?0.54%) and BuChE (98.98?±?0.17%), with an IC₅₀ value of 59.31?±?0.35 and 51.72?±?0.33?µg/ml, respectively. Among the different solvent extracts, methanolic extract exhibited the highest antioxidant activity with an IC₅₀ value of 47.39?±?0.43, 401.45?±?18.52, 80.23?±?0.70, and 316.47?±?3.56?µg/ml for DPPH, hydroxyl, nitric oxide radical, and hydrogen peroxide, respectively. Total polyphenolic and flavonoid contents in methanolic extract were observed to be 598.13?±?1.85?µg of gallic acid equivalent and 48.85?±?0.70?μg of rutin equivalent/mg of extract. Compound characterization illustrated (+)-catechin as the bioactive compound responsible for cholinesterase inhibitory and antioxidant activities.

Conclusion: The presence of rich source of flavonoids, in particular catechin, might be responsible for its cholinesterase inhibitory and antioxidant activities.     

Novel 16-substituted bifunctional derivatives of huperzine B： multifunctional cholinesterase inhibitors

Aim： To design novel bifunctional derivatives of huperzine B （HupB） based on the concept of dual binding site of acetylcholinesterase （ACHE） and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer＇s disease （AD）. Methods： Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase （BuChE） were determined in vitro by modified EIIman＇s method. Cell viability was quantified by the reduction of MTT. Results： A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide （H2O2）-induced cytotoxicity in PC12 cells. Conclusion： Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clini- cal efficacies.     

抗阿尔茨海默病的胆碱酯酶抑制剂研究进展

目前抗阿尔茨海默病的新策略之一是设计具有多靶向的药物。综述抗阿尔茨海默病的胆碱酯酶抑制剂研究的新进展,分类介绍乙酰胆碱酯酶和丁酰胆碱酯酶双重抑制剂、可抑制B-淀粉样蛋白聚集的胆碱酯酶抑制剂、具有抗氧化作用的胆碱酯酶抑制剂、可拮抗H,受体的胆碱酯酶抑制剂以及NO供体型胆碱酯酶抑制剂等多靶向药物,并讨论了各类药物的设计和优化。     

阿尔茨海默病的诊断进展

阿尔茨海默病（AD）是一种与年龄相关的以进行性认知功能损害为主要表现的神经变性疾病,是痴呆的主要原因。目前,AD的诊断标准仍在不断深入研究和修订中。本文综述AD的最新诊断标准、评估量表及生物标志物三方面的进展。     

四乙胺对Aβl-40致伤的神经干细胞的存活及其Caspase-3表达的影响

目的探讨钾通道阻滞剂四乙胺(tetraethy-lammonium,TEA)在Aβl-40致伤的神经干细胞增殖及凋亡中的作用。方法 Aβl-40与神经干细胞共孵育,诱导神经干细胞损伤,以TEA作用于Aβl-40致伤的神经干细胞,利用MTT法和比色法分别检测神经干细胞在不同的时间点的存活率及Caspase-3活性。结果 Aβl-40可使神经干细胞的存活率降低,呈时间依赖性;Aβl-40与神经干细胞在不同的时间点共孵育后,Caspase-3活性逐渐增加,在24h达到高峰;加入TEA后,Aβl-40致伤的神经干细胞的存活率增加,Caspase-3活性表达下降。结论 Aβl-40对神经干细胞的致伤作用可能与钾通道的激活相关,TEA能够降低Aβl-40对神经干细胞的致伤作用,减少神经干细胞的凋亡为治疗阿尔茨海默病提供了新的方法。     

茚酮氨基甲酸酯衍生物的设计合成及其对乙酰胆碱酯酶抑制活性的研究

目的设计合成茚酮氨基甲酸酯衍生物并进行乙酰胆碱酯酶(AChE)抑制活性测试。方法以羟基苯丙酸为起始原料,经分子内Friedel-Crafts酰化、羟基的氨基甲酸酯化和羟醛缩合3步反应合成目标物;采用Ellman法,以拉多替吉(ladostigil)为阳性对照,测试目标化合物对AChE的抑制活性。结果合成了8个未见文献报道的新化合物,其结构和纯度均经1H-NMR、MS谱测定。结论目标化合物对AChE均表现出一定的抑制活性,可作为先导化合物做进一步的改造和修饰。     

Synthesis,in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery

New glycosyl derivatives of ibuprofen (I, II, III, and IV) were synthesized in order to overcome the ineffective delivery of ibuprofen across the blood–brain barrier owing to its low permeability, using d-glucose as a drug targeting agent. Ibuprofen was linked directly to the C-2, C-3, C-4, and C-6 positions of glucose via ester bonds. Furthermore, in vitro stabilities of the four ester derivatives were evaluated to determine both their stability in aqueous medium and their feasibility to undergo enzymatic cleavage by esterase in biological samples to regenerate the original drug. From the obtained results, compounds I–IV appeared to be moderately stable in pH 7.43 buffer solution, rat plasma, and brain tissue extracts. In vivo experiments showed that the AUC_0–t of ibuprofen in plasma after the injection of prodrugs is several times higher than that of AUC_0–t after the injection of ibuprofen. In addition, the maximal concentration of ibuprofen in brain after the administration of ester IV was three fold higher than that of the control group. Also, the concentration of ibuprofen was kept stable in brain for about 4?h for four esters, which was beneficial for the treatment of Alzheimer’s disease and highlighted the possibility of brain drug delivery of ibuprofen using prodrug strategies.     

新型阿魏酸类衍生物的设计、合成及对LPS诱导N9小胶质细胞激活的抑制作用研究

目的设计合成一系列阿魏酸衍生物并测定其体外抑制LPS激活N9小胶质细胞的活性。方法以香兰素为起始原料,经Knoevenagel反应,与美金刚胺盐酸盐直接缩合得基本母核结构(AMJ),再经Mannich反应得到8个目标化合物。采用建立体外LPS激活N9小胶质细胞异常活化的筛选模型对合成的目标化合物活性进行评价。结果合成了8个未见报道的新化合物,其结构经MS及1H-NMR谱确证。活性实验结果表明,化合物4a⁴g能够显著抑制LPS刺激的N9小胶质细胞NO释放,在其发挥抑制作用的浓度范围内不影响小胶质细胞存活率。结论阿魏酸衍生物可能具有减轻小胶质细胞活化介导的神经系统疾病(如神经退行性疾病)的潜在作用。