小檗红碱及其衍生物的研究进展

小檗红碱属于异喹啉类生物碱,是小檗碱的主要代谢产物,小檗碱在一定的加热条件下可以大量转化为小檗红碱.小檗红碱在中药材黄连和黄柏中含量较低,具有抗肿瘤、抗炎、抗菌、降糖、降脂等作用.小檗红碱在体内吸收迅速,可广泛分布于各种组织中,以肝脏代谢为主.随着小檗红碱的药理活性和用药安全受到广泛关注,本文作者在参考最新最全面的文献...     

小檗碱的药理活性以及提升其口服生物利用度的策略

小檗碱(berberine)是一种天然存在的苄基异喹啉类生物碱,具有抗菌、抗癌、降血脂、抗糖尿病和止泻等广泛药理活性,但因其极低的口服生物利用度(<1%),限制了其在临床上的应用,尚无纯小檗碱配方被批准用于任何特定疾病。小檗碱口服生物利用度低主要是由于其在酸性条件下自聚集导致的溶解度差、渗透性低、P-gp(P-glycoprotein)介导的外排和肝肠代谢。提高小檗碱的口服生物利用度可提高小檗碱的药理活性,降低给药剂量进而减少不良反应。本文综述了小檗碱的多种药理活性、代谢过程、药代动力学特征,重点介绍了通过提高溶解度和渗透性、抑制P-gp外排和结构修饰等途径提高小檗碱口服生物利用度的策略,并对小檗碱的研究进行了展望,为其深入研究提供指导。     

小檗碱的结构修饰及其药理学活性研究进展

小檗碱类化合物是异喹啉生物碱中一个重要组成部分,其生理功能广泛,对其构效关系的研究较多,具有很大的结构改造和修饰的空间。本文按其主要药理学活性,对小檗碱及其衍生物的结构修饰进展作一综述。     

小檗碱抗球菌的药理作用研究进展

小檗碱具有抗多种葡萄球菌、链球菌和其他球菌的作用。小檗碱能多靶点地作用于细菌,干扰糖脂代谢、氨基酸代谢、核酸代谢和蛋白质代谢,以及破坏细菌细胞膜和细胞壁结构,小檗碱不仅使细菌不易产生耐药性,而且能降低细菌对其他药物的耐药性,增强其他抗菌药物的抗菌活性。游离态小檗碱是一种弱碱,其抗菌作用远强于离子态小檗碱,因此在使用小檗碱时应尽可能使其在弱碱性环境下发挥作用。笔者综述与分析了小檗碱抗球菌的药理作用研究进展。     

盐酸小檗碱的心血管药理活性研究进展

小檗碱是一种异喹啉生物碱,存在于黄连、黄檗等植物中,临床常用其盐酸盐.盐酸小檗碱具有强心、抗心律失常、内皮保护、心肌保护、降压、抗动脉粥样硬化、糖尿病性心血管疾病治疗等心血管药理活性作用,是一种富有潜力的心血管疾病治疗药物.本文通过对PubMed数据库进行检索,对盐酸小檗碱的心血管药活性研究进行了综述.     

血根碱、白屈菜红碱衍生物的合成与体外抗HBV活性研究

目的合成季铵类苯并菲啶生物碱血根碱(1)和白屈菜红碱(2)的衍生物,评价其体外抗HBV活性,初步探讨抗HBV活性。方法以血根碱和白屈菜红碱为原料,通过结构修饰获得衍生物,采用Hep G2.2.15细胞模型评价衍生物对HBsAg和HBeAg分泌抑制活性和HBV DNA复制的抑制活性。结果血根碱和白屈菜红碱对HBsAg、HBeAg和HBV DNA复制具有较高的抑制活性,但细胞毒性较高。氧化白屈菜红碱(6)对HBV DNA的复制具有一定的抑制作用(IC50=0.75 mmol·L-1),细胞毒性较白屈菜红碱明显降低(CC50>3.0 mmol·L-1)。6-乙氧基二氢血根碱(7)和6-乙氧基二氢白屈菜红碱(8)对HBsAg和HBeAg和HBV DNA复制具有一定的抑制活性。结论季铵类苯并菲啶生物碱具有显著的体外抗HBV活性,烯胺正离子结构单元对化合物的抗HBV活性产生重要的影响。     

小檗碱的抗病原生物作用研究进展

小檗碱又名黄连素,具有非常广泛的药理活性,但其准确的作用靶点至今不清.本文主要综述其抗病毒作用、抗细菌作用、抗真菌作用及其作用的构效关系和分子机制,对揭示生命现象的本质,发现新药靶点具有重要意义,也为小檗碱的结构优化改造和应用研究提供新的线索.     

小檗碱烷基修饰物与细菌质粒DNA作用的荧光分析

目的为深入了解小檗碱与生物大分子核酸的作用关系,探讨小檗碱类化合物的分子药理机制方法采用荧光分析技术观察小檗碱及其8-烷基修饰物与质粒DNA作用后的荧光光谱变化规律。结果与小檗碱比较,短链烷基（乙基、丁基、己基和辛基）修饰后的小檗碱衍生物与质粒DNA作用后的荧光强度增强,其中8-丁基小檗碱表现出最强作用,长链烷基（十二烷基、十六烷基）则相反。同时发现,所有小檗碱烷基修饰物与细菌质粒DNA的最佳作用浓度与小檗碱一样,均为6.25×10-5mol.L-1。结论短链烷基的接入有利于小檗碱与质粒DNA的作用强度,烷基修饰并没有改变药物分子与DNA的作用位点数,只是增强了相互之间的作用强度。     

小檗碱类抗微生物化合物研究进展

小檗碱类化合物是一类具有多种生物活性且大量应用于临床的季铵类异喹啉生物碱。近年来,小檗碱类药物的研究与开发受到广泛关注,且逐渐成为一个发展迅速、充满活力的领域。通过结构修饰所得的小檗碱类衍生物具有良好的抗细菌、抗真菌及抗病毒活性,可通过多种靶点对微生物发挥抑制作用。本文综述小檗碱类衍生物在抗细菌、抗真菌及抗病毒方面的研究与开发进展状况,为进一步研发小檗碱类抗微生物药物提供参考。     

9-位引入亲脂性芳基对小檗碱抗菌活性的影响

目的 研究小檗碱9位引入亲脂性芳基后,其抗菌活性的变化。方法在小檗碱9位引入苯氧丁基,提高小檗碱的脂溶性,并采用体外抑菌实验,与小檗碱的抗菌活性进行对比。结果体外抑菌实验表明,在小檗碱9位引入亲脂性苯氧丁基后,其对¨种常见细菌的的最低抑菌浓度比小檗碱分别降低了4～16倍。结论9位引入亲脂性芳基增强了小檗碱的抗菌活性。     

Multitargeted C9-substituted ester and ether derivatives of berberrubine for Alzheimer's disease: Design,synthesis, biological evaluation,metabolic stability,and pharmacokinetics

Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget-directed ligands have the potential as disease-modifying therapeutics. Herein, we prepared a series of C9-substituted berberrubine derivatives intending to discover dual cholinesterase and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE-1. Two most active ester derivatives, 12a and 11d , display inhibition of AChE, BChE, and BACE-1. The 3-methoxybenzoyl ester derivative, 12a , inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE-1 with IC₅₀ values of 0.5, 4.3, and 11.9 μM, respectively and excellent BBB permeability (P_e = 8 × 10⁻⁶ cm/s). The ester derivative 12a is metabolically unstable; however, its ether analog 13 is stable in HLM and exhibits inhibition of AChE, BChE, and BACE-1 with IC₅₀ values of 0.44, 3.8, and 17.9 μM, respectively. The ether analog also inhibits self-aggregation of Aβ and crosses BBB (P_e = 7.3 × 10⁻⁶ cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC_0−∞ of 28,834 ng min/ml. In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.     

Antimicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines

In the course of a structure-activity relationship study on berberrubine derivatives, a series of compounds bearing 9-O-acyl-(4-6) and 9-O-benzoyl- (7) substituents was synthesized with the expectation of increasing the antimicrobial activity. One of the berberrubine derivatives, 9-lauroylberberrubine chloride was the most active against Gram-positive bacteria Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus subtilis as well as the Gram-negative bacterium Klebsiella pneumoniae in comparison to berberine, the currently used antibiotic in clinic. This result suggested that the presence of lipophilic substituents of certain structures and sizes might be crucial for the optimal antimicrobial activity.     

The metabolism of berberine and its contribution to the pharmacological effects

Berberine, a bioactive alkaloid isolated from several herbal substances, possesses multiple pharmacological effects, including antimicrobial, antidiabetic, anticancer activities. Meanwhile, berberine undergoes extensive metabolism after oral administration which results in its extremely low plasma exposure. Therefore, it is believed that the metabolites of berberine also contribute a lot to its pharmacological effects. Along these lines, this review covers the metabolism studies of berberine in terms of its metabolic pathways and metabolic organs based on the identified metabolites, and it also covers the pharmacological activities of its active metabolites. In brief, the predominant metabolic pathways of berberine are demethylation, demethylenation, reduction, hydroxylation and subsequent conjugation in vivo. Active metabolites such as columbamine, berberrubine and demethyleneberberine also exhibit similar pharmacological effects by comparison with berberine, such as antioxidant, anti-inflammatory, antitumor, antimicrobial, hepatoprotective, neuroprotective, hypolipidemic and hypoglycemic effects. Overall, berberine together with its metabolites formed the material basis of berberine in vivo.     

Studies on Indonesian medicinal plants VI further alkaloids from Fibraurea chloroleuca

From the stem and root bark of FIBRAUREA CHLOROLEUCA M IERS the alkaloids magnoflorine, pseudocolumbamine, dehydrocorydalmine and palmatrubine were isolated and identified by their spectral data. By means of TLC the alkaloids berberine and berberrubine were found to be present in minute amounts.     

肠道微生物次级代谢产物及疾病治疗的研究现状

肠道微生物次级代谢产物化学结构新颖、生物活性多样。目前发现的肠道微生物代谢产物主要包括环二肽及多肽类、生物碱类、内酯类、环酰胺类等,肠道微生物在抗菌、抗病毒、抗炎等方面表现出巨大的研究前景。本文对近几年来肠道微生物来源的次级代谢产物的结构特征、生物活性及肠道微生物在疾病治疗方面的研究进展进行总结和综述。     

Hydroxyl radical scavenging activities of isoquinoline alkaloids isolated from <Emphasis Type="Italic">Coptis chinensis</Emphasis>

The hydroxyl radical (•OH) scavenging and ferrous ion chelating activities of four isoquinoline alkaloids isolated from Coptis chinensis Franch were studied for the identification of their structural characteristics to scavenge •OH. The •OH was generated via Fe(II)-catalazed Fenton reaction in this study and the reliable measurement of •OH scavenging activities of isoquinoline alkaloids were achieved using electron spin resonance (ESR) spectrometry method. At the 1 mM concentration, berberrubine (85%) showed the strongest •OH scavenging activity and the next were in the decreasing order of coptisine (79%), berberine (23%), and palmatine (22%). The ferrous ion chelating effects of the alkaloids showed similar pattern with their •OH scavenging effects. These results suggest that •OH scavenging effects of the alkaloids were closely related to their ferrous ion chelating activities. In addition, metal chelating functional groups such as hydroxy group at C-9 and methylenedioxy group at C-9 and C-10 were thought to contribute to the •OH scavenging activities of the isoquinoline alkaloids.     

呫吨酮类化合物的药理活性研究进展

目的:综述近年来呫吨酮类化合物的药理活性研究进展.方法:收集国内外有关文献汇总.结果:呫吨酮类化合物具有多方面的药理活性:抗疟作用;保肝及治疗急慢性肝炎的作用;抗氧化作用;抗结核作用;抗抑郁活性;治疗热症、肝胆病及血液病;抗心肌缺血作用等.结论:呫吨酮类化合物具有多种药理活性,是一类很有发展空间的活性天然产物,药理学研究还存在很多不足,需要进一步研究.     

Interaction of six protoberberine alkaloids with human organic cation transporters 1, 2 and 3

1.?Organic cation transporters (OCTs) play an important role in drug safety and efficacy. Protoberberine alkaloids are ubiquitous organic cations or weak bases with remarkable biological actives. This study was to elucidate the potential interaction of alkaloids (coptisine, jatrorrhizine, epiberberine, berberrubine, palmatine and corydaline) with OCTs using Madin–Darby canine kidney (MDCK) cells stably expressing human OCT1, OCT2 and OCT3.

2.?All the tested alkaloids significantly inhibited the uptake of MPP⁺, a model OCT substrate, in MDCK-hOCTs cells with the IC₅₀ of 0.931–9.65?μM. Additionally, coptisine, jatrorrhizine and epiberberine were substrates of all the hOCTs with the K_m of 0.273–5.80?μM, whereas berberrubine was a substrate for hOCT1 and hOCT2, but not for hOCT3, the K_m values were 1.27 and 1.66?μM, respectively. The transport capacity of coptisine in MDCK cells expressing the variants of hOCT1-P341L or hOCT2-A270S was significantly higher than that in wild-type (WT) cells with the Cl_int (V_max/K_m) of 379?±?7.4 and 433?±?5.7?μl/mg protein/min, respectively.

3.?The above data indicate that the tested alkaloids are potent inhibitors, and coptisine, jatrorrhizine, epiberberine and berberrubine are substrates of hOCT1, hOCT2 and/or hOCT3 with high affinity. In addition, the variants (OCT1-P341L and OCT2-A270S) possess higher transport capacity to coptisine than WT hOCTs.     

有机硒潜在药物的研究进展

有机硒药物是一类新型化合物,由于其具有抗病毒、抗肿瘤以及治疗神经系统方面疾病的作用,已成为药物研究的热点。研究表明,有机硒类化合物还具有抗炎、抗衰老、防治心血管疾病及预防肝部疾病等药理作用。由于硒具有独特的生化性质和药理作用,因此开发含硒类药物极具意义。该文就近年来有机硒潜在药物的研究情况进行综述。