小檗红碱药理作用及其结构修饰研究进展

天然来源的小檗红碱具有多种药理活性,对于其药物活性及结构修饰多有报道.本文围绕小檗红碱抗癌、抗炎、抗神经系统疾病、抗心血管疾病、抗真菌、抗糖尿病方面进行综述.同时对其结构修饰也作概述,为小檗红碱合理开发利用提供参考.     

Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016)

Introduction: Ursolic acid (UA), belongs to a group of pentacyclic triterpenoids and is known to possess some very interesting biological properties. Protocols have been developed in order to synthesize bioactive UA analogs which have resulted in numerous ursolic acid analogs being synthesized during the period 2012–2016. Ursolic acid and its analogues can be employed to treat various cancers, inflammatory diseases, diabetes, Parkinson’s disease, Alzheimer’s disease, hepatitis B, hepatitis C and AIDS to mention but a few.

Areas covered: This review covers patents on therapeutic activities of ursolic acid (UA) and its synthetic derivatives published during the four year period 2012–2016. A discussion about structure-activity relationships (SAR) of these analogs is also included.

Expert opinion: Ursolic acid and its synthetic derivatives demonstrated excellent anticancer, antidiabetic, antiarrhythmic, anti-hyperlipidemic, antimicrobial, anti-hypercholesterolemic, and anti-cardiovascular properties. Additionally, various ursolic acid analogues have been synthesized through modification at positions C₂-OH, C₃-OH and C_17-CO₂H. It is noteworthy that the C-17 amide and amino analogs of UA possessed better anticancer activity compared to the parent compound (UA). Most importantly, UA has the potential to conjugate with other anticancer drugs or be transformed into its halo derivatives since this will greatly facilitate scientists to get lead compounds in cancer drug discovery.     

聚乙二醇缀合熊果酸衍生物的合成及体外抗癌活性

目的:合成具有一定水溶性的聚乙二醇(PEG)缀合熊果酸衍生物并考察其体外抗癌活性。方法:以熊果酸(ursolic acid,UA)作为母核,采用PEG、琥珀酸对其C28位进行接合修饰,合成一系列PEG缀合熊果酸衍生物并考察其水溶性和抗癌活性;采用流式细胞术探讨其抗癌机制。结果:所合成系列PEG缀合熊果酸衍生物的水溶性较熊果酸有明显改善,同时具有更显著的体外抗癌活性;化合物8c对5株受试肿瘤细胞的IC50(48 h)均小于10μmol.L-1,将AGS细胞阻滞于G2/M期并具有诱导凋亡作用(凋亡率高于70%)。结论:将熊果酸C28位进行PEG修饰是保持和提高其抗癌活性的有效途径之一。     

Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid‐ and Multidrug‐resistant Escherichia coli

As a part of our drug discovery program, ursolic acid was chemically transformed into six semi‐synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid‐sensitive and nalidixic acid‐resistant strains of Escherichia coli. Although ursolic acid and its all semi‐synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3‐O‐acetyl‐urs‐12‐en‐28‐isopropyl ester (UA‐4) and 3‐O‐acetyl‐urs‐12‐en‐28‐n‐butyl ester (UA‐5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid‐resistant and four and eightfold against nalidixic acid‐sensitive, respectively. The UA‐4 and UA‐5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug‐resistant clinical isolate of Escherichia coli‐KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration‐dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA‐4 and UA‐5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug‐resistant Gram‐negative infections.     

Usnic acid and its derivatives for pharmaceutical use: a patent review (2000–2017)

Introduction: Usnic acid (UA) is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton and is commonly found in lichenized fungi of the genera Usnea and Cladonia. Usnic acid has been incorporated for years in cosmetics, perfumery, and traditional medicines. It has a wide range of bioactivities, including antimicrobial, antiviral, anticancer, anti-inflammatory properties.

Areas covered: This review covers patents on therapeutic activities of UA and its synthetic derivatives published during the period 2000–2017.

Expert opinion: UA demonstrates excellent anticancer and antimicrobial properties. However, its application was withdrawn due to acute liver toxicity reported with chronic consumption. The broad spectrum of its biological activity indicates high the variability of UA’s binding preferences. The main idea to be addressed in the future should include the synthesis of UA derivatives because these might possess increased bioactivity, bioavailability and decreased toxicity. It is noteworthy that UA derivatives possessed better antibacterial, antitubercular, and anticancer activity than the parent compound . Most importantly, UA and its analogs (to a greater extent than UA) can be useful in cancer drug treatment. They have the potential for joint application with other anticancer drugs in order to overcome drug resistance.     

Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs

Ursolic acid ( UA ) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and ¹H NMR. The ability of the UA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non‐pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors than UA . In particular, 5b demonstrated IC₅₀ values ranging from 4.09 ± 0.27 to 7.78 ± 0.43  μ m against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin‐dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose‐dependent manner.     

抗糖尿病药物的临床用药分析

目的 分析医院抗糖尿病药物的使用情况,为临床合理用药提供依据.方法 运用医院药库计算机网络系统对我院2007-2009年所用的抗糖尿病药物品种、金额和用药频度等数据进行统计学分析.结果 抗糖尿病药物的销售金额呈逐年上升趋势,在我院药物总销售金额所占比例逐渐增加.其中胰岛素类药物在所有抗糖尿病药物的销售中占有率最大,3年的销售金额分别为30.21万元、126.93和246.58万元.阿卡波糖、二甲双胍和格列美脲是我院使用的主要口服抗糖尿病药物.结论 糖尿病的致病因素很多,主要和胰岛素分泌或生成异常有关.抗糖尿病药物市场潜力大,安全、有效、依从性好、价格适中的药物是糖尿病治疗药物的必然发展趋势.

Abstract：

Objective To analyze the clinical application status of anti-diabetes agent used in our hospital, and to provide reference for clinical application. Methods The anti-diabetes drugs variety, amount and the frequency of drug usage and other data from 2007 to 2009, were statistically analyzed using internet methods. Results The sales revenue of the anti-diabetes drugs increased from year to year, and its sales proportion among all drugs in the hospital was gradually increasing at the same time. The sales revenue of the insulin-type drugs was the largest and increased every year. Acarbose, metformin and glimepiride were the main oral anti-diabetes drugs in our hospital. Conclusions Anti-diabetes drugs have big market potential. The drugs that are safe, effective with good compliance and moderate prices are the majority of diabetes-treating drugs.     

Anti-hepatocellular carcinoma activity and mechanism of chemopreventive compounds: ursolic acid derivatives

Context: Hepatocellular carcinoma (HCC) is a common cancer around the world, with high mortality rate. Currently, there is no effective drug for the therapy of HCC. Ursolic acid (UA) is a natural product which exists in various medicinal herbs and fruits, exhibiting multiple biological effects such as its outstanding anticancer and hepatoprotective activity, which has drawn many pharmacists’ attention.

Objective: This paper summarizes the current status of the hepatoprotective activity of UA analogues and explains the related mechanism, providing a clear direction for the development of novel anti-HCC drugs.

Methods: All of the data resources were derived from PubMed. By comparing the IC₅₀ values and analyzing the structure–activity relationships, we listed compounds with good pharmacological activity from the relevant literature, and summarized their anti-HCC mechanism.

Results: From the database, 58 new UA derivatives possessing wonderful anticancer and hepatoprotective effects were listed, and the relevant anti-HCC mechanism were discussed.

Conclusion: UA’s anti-HCC effect is the result of combined action of many mechanisms. These 58 new UA derivatives, particularly compounds 45 and 53, can be used as potential drugs for the treatment of liver cancer.     

Estrogenic and contraceptive activity of 17-R-hydroximino derivatives of 9alpha-hydroxy-11beta-nitroxyestrones

The estrogenic or uterotropic (UA) and contraceptive (CA) activity of two modified steroids representing 17-R-oximino-9 alpha-oxy-11 beta-nitroxyestrone derivatives (compounds I and II) was experimentally studied by oral administration in female rats in comparison to ethynylestradiol (EED) and mestranol. Compounds I and II showed significant UA (about half that of EED and mestranol) and a pronounced contraceptive effect (exceeding that of mestranol). The dissociation of the drug effects for CA is also indicated by the index of contraception (IC) or the CA/UA ratio. The administration of compounds I and II did not lead to a loss of animals in the acute toxicity tests on female mice.     

由降糖中成药和保健食品检验情况探索非法添加化学成分的系统快筛思路

本文分析了中成药及保健食品中非法添加降糖成分常是复合添加的特点,探索系统快筛思路,可指导建立一种对常见添加降糖成分的中成药及保健食品进行检测的快筛方法,具有提高检验的覆盖率和节省检验资源的优点。     

亚麻木酚素的药理作用研究进展

亚麻木酚素主要来源于亚麻籽,具有显著的生物活性。亚麻木酚素具有抗氧化作用、抗炎作用、抗肿瘤作用、抗心血管疾病、抗骨质疏松作用、抗凋亡作用、降糖作用等。综述了亚麻木酚素药理作用的研究进展,以期为亚麻木酚素的研究和开发利用提供依据。     

GLP-1受体激动剂和DPP-4抑制剂对心血管系统的保护作用

胰高糖素样肽1(GLP-1)受体激动剂和二肽基肽酶-4(DPP-4)抑制剂是近年上市的治疗2型糖尿病的新型药物。GLP-1主要通过抑制心肌细胞凋亡、改善内皮细胞功能、减轻体重、降低血糖、降低血压、改善心肌收缩力、舒张血管等直接或间接发挥其心脏保护作用,GLP-1受体激动剂和DPP-4抑制剂对体重、血压和血脂等心血管危险因素有改善作用。GLP-1受体激动剂和DPP-4抑制剂作用于新靶点,具有其独特的优点,将会是一类抗糖尿病新药。     

糖泰胶囊的药效学研究

目的探讨糖泰胶囊的临床疗效机制。方法对糖泰胶囊进行药效学实验研究。结果糖泰胶囊有显著的降血糖和增加肝糖元作用,对血清胰岛素含量水平有一定的升高作用。结论本品是一良好的降糖中药制剂。     

The association between the measurement of adherence to anti-diabetes medicine and the HbA1c

Background Adherence to medicines is important in subjects with diabetes, as nonadherence is associated with an increased risk of morbidity and mortality. However, it is not clear whether there is an association between adherence to medicines and glycaemic control, as not all studies have shown this. One of the reasons for this discrepancy may be that, although there is a standard measure of glycaemic control i.e. HbA1c, there is no standard measure of adherence to medicines. Adherence to medicines can be measured either qualitatively by Morisky or non-Morisky methods or quantitatively using the medicines possession ratio (MPR). Aims of the review The aims of this literature review are (1) to determine whether there is an association between adherence to anti-diabetes medicines and glycaemic control, and (2) whether any such association is dependent on how adherence is measured. Methods A literature search of Medline, CINAHL and the Internet (Google) was undertaken with search terms; ‘diabetes’ with ‘adherence’ (or compliance, concordance, persistence, continuation) with ‘HbA1c’ (or glycaemic control). Results Twenty-three studies were included; 10 qualitative and 12 quantitative studies, and one study using both methods. For the qualitative methods measurements of adherence to anti-diabetes medicines (non-Morisky and Morisky), eight out of ten studies show an association with HbA1c. Nine of ten studies using the quantitative MPR, and two studies using MPR for insulin only, have also shown an association between adherence to anti-diabetes medicines and HbA1c. However, the one study that used both Morisky and MPR did not show an association. Three of the four studies that did not show a relationship, did not use a range of HbA1c values in their regression analysis. The other study that did not show a relationship was specifically in a low income population. Conclusions Most studies show an association between adherence to anti-diabetes medicines and HbA1c levels, and this seems to be independent of method used to measure adherence. However, to show an association it is necessary to have a range of HbA1c values. Also, the association is not always apparent in low income populations.     

The uric acid metabolism pathway as a therapeutic target in hyperuricemia related to metabolic syndrome

Introduction: Uric acid (UA) increase is considered an important risk factor for the development of cardiovascular disease (CVD) favoring oxidative stress and endothelial dysfunction and is also involved in metabolic syndrome (MS) pathophysiology.

Areas covered: Insulin has a physiological action on renal tubules, causing a reduction in UA clearance, what could explain the hyperuricemia found in MS. On the other hand, it was also hypothesized a causal role of UA in fructose-induced MS. Moreover, it has been suggested that higher UA levels predict the development of MS. MS subjects present a redox imbalance and UA participates in this process. UA can contribute to oxidative stress present in MS; however, it has also an important role in the antioxidant defense system. Although UA may have a protective effect due to its antioxidant properties, it is clear that the dominant effect of UA in MS is deleterious. All-cause mortality and CVD have been shown to be increased with higher UA levels.

Expert opinion: It is extremely important to prescribe drugs which concomitantly decrease hyperuricemia and improve co-morbidities associated with hyperuricemia. Long-term studies to verify the consequences of decreasing UA concentration below current recommendations in asymptomatic patients are needed.     

Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism

The natural product oleanolic acid (OA) has been discovered to exhibit varied pharmacological functions including anti-inflammation, anti-tumor and anti-diabetes, while appropriate synthetic oleanolic acid derivatives seem to possess more potent activities. Here we identified a new oleanolic acid derivative, 3-β-(2-carboxybenzoyloxy)-oleanolic acid (NPLC441), which functioned as a competitive PTP1B inhibitor and enhanced insulin-stimulated phosphorylation of IR and AKT in HepG2 cells. As an RXRα antagonist, it could selectively activate LXRα:RXRα heterodimer and increase the promoter activities of ABCA1 and ABCG1 genes in transient transfection assays. Quantitative RT-PCR and Western blot analyses suggested that NPLC441 could up-regulate GLUT4 expression in 3T3-L1 adipocytes, and such effect was further proved to be dependent on LXRα:RXRα activation. Moreover, 2-deoxyglucose uptake technology-based characterization demonstrated that this compound could stimulate glucose uptake in 3T3-L1 adipocytes. Finally, NPLC441 was observed to be able to suppress 11β-HSD₁ expression in HepG2 cells, following the discovery that activation of LXRα:RXRα could repress the expression of 11β-HSD₁. Compared with NPLC441, OA showed no effects on the transactivation of either LXRα:RXRα heterodimer or RXRα-LBD. Our work is thus expected to provide a new insight into the anti-diabetic application for oleanolic acid derivatives via multi-target mechanism, and NPLC441 could be used as a potential lead compound for further research.     

Evaluation of endogenous urinary biomarkers for indirect detection of urine adulteration attempts by five different chemical adulterants in mass spectrometry methods

Reliable detection of urine adulteration attempts to circumvent positive drug testing represents a critical step for laboratories in abstinence control settings. An ideal workflow for high‐throughput testing would involve simultaneous detection of adulteration attempts in the same run with drug detection. Monitoring of degraded or oxidized endogenous urinary compounds as indirect markers has been previously evaluated for that purpose exemplified for the adulterant potassium nitrite (KNO₂). Fifteen, previously identified endogenous markers should now be evaluated for their general applicability to detect adulteration attempts for the adulterants hypochlorite‐based bleach (NaOCl), peroxidase and peroxide (H₂O₂), pyridinium chlorochromate (PCC), and iodine (I₂). Initial experiments revealed similar results for the tested adulterants regarding degradation of indolylacryloylglycine (IAG), uric acid (UA), or UA derivatives. 5‐Hydroxyisourate (HIU), the oxidation product of UA, was however only formed by KNO₂, PCC, and H₂O₂. Amino acids showed larger adulterant‐dependent differences. All reactions were shown to be influenced by the adulterant concentration and the urinary pH with large variances depending on compound and adulterant. Except for HIU/PCC, all markers were stable within +/? 30% variation for all adulterants at ?20°C. Receiver operating characteristics indicated best sensitivity and specificity over all adulterants for IAG (specificity 0.9, sensitivity 1.0) and UA (specificity 1.0, sensitivity 0.9). HIU gave best results for KNO₂, PCC, and H₂O₂ and N‐acetylneuraminic acid for PCC and H₂O₂, respectively. When integrating a limited number of targets into existing screening methods, monitoring of UA, IAG, N‐acetylneuraminic acid, and HIU is recommended.     

Improved Pharmacokinetic Characteristics of Ursolic Acid in Rats Following Intratracheal Instillation and Nose-Only Inhalation Exposure

Ursolic acid (UA) is a common pentacyclic triterpene phytochemical with various pharmacological activities. However, UA is classified as a class IV drug in BCS system and its development as an oral drug is limited. Pulmonary delivery is an effective way to improve the bioavailability of drugs with low absorption. In this study, the differences in pharmacokinetic behaviors of UA after pulmonary and oral administration was explored in rats. Compared with oral administration, the plasma concentration of UA increased rapidly after pulmonary administration, and the bioavailability increased about 80 times. UA instantly accumulated in the lungs after pulmonary administration, and the pulmonary AUC_0-t/dose increased by 114 times compared to oral dosing. Incubation experiments showed that the metabolism of UA in rat lung microsomes was significantly reduced compared with that in liver microsomes, in which the clearance rate of phase I and phase II metabolism was reduced by 14.7 times and 1.4 times respectively. These results indicated that pulmonary administration could improve the bioavailability of UA and reduce its metabolism. This study not only provides a preferable route of administration for the application of UA but also offers new insights for the development of phytochemical drug candidates with poor pharmacokinetic properties.     

溶血磷脂酸对于评估不稳定心绞痛患者不良预后的临床意义

目的：探讨溶血磷脂酸（ LPA）对于不稳定心绞痛（ UA）患者不良预后的临床意义。方法纳入该院心血管内科于2012年7月1日至2013年7月1日期间收治尚处于UA阶段的非ST段抬高型急性冠状动脉综合征（ NSTE-ACS）患者,收集相关危险因素的临床资料,并进行随访以确认预后转归。分析不同预后各项指标的差异性,并评判敏感指标的预后相关性。结果与未转归至NSTEMI（ UA组）相比,NSTEMI组患者的LPA等12项危险因素存在显著差异,经多因素Logistic回归分析得出年龄（ Age）、心肌梗死溶栓试验危险评分（ TIMI）、低密度脂蛋白胆固醇（ LDL-C）、脂联素（ APN）、LPA这5项指标是UA预后转归为NSTEMI的独立、敏感影响因素。其中LPA用于判定UA不良预后的AUC为0．731,联合其余4项指标判定UA不良预后的AUC为0．831,加入LPA后AUC增加至0．854。结论 LPA水平可作为评判UA预后的独立敏感因素,其含量变化对于UA进展至NSTEMI息息相关,将LPA纳入UA的诊疗体系以用于干预高危风险患者具有重要临床意义。