Aporphine alkaloids and their reversal activity of multidrug resistance (MDR) from the stems and rhizomes ofSinomenium acutum

Chromatographic separation of the MeOH extract from the stems and rhizomes of Sinomemium acutum led to the isolation of nine alkaloids and a lignan. Their structures were determined to be dauriporphine (1), bianfugecine (2), dauriporphinoline (3), menisporphine (4), (-)-syringaresinol (5), N-feruloyltyramine (6), acutumine (7), dauricumine (8), sinomenine (9), and magnoflorine (10) by spectroscopic means. These compounds were examined for their P-gp mediated MDR reversal activity in human cancer cells. Compound 1 showed the most potent P-gp MDR inhibition activity with an ED50 value 0.03 microg/mL and 0.00010 microg/mL in the MES-SA/DX5 and HCT15 cells, respectively.     

Isolation of limonoids and alkaloids from<Emphasis Type="Italic">Phellodendron amurense</Emphasis> and their multidrug resistance (MDR) reversal activity

Three limonoids and five alkaloids were isolated from the chloroform layer of the MeOH extract of the bark of Phellodendron amurense (Rutaceae). The structures of the compounds isolated were determined to be obacunone (1), limonin (2), 12alpha-hydroxylimonin (3), gamma-fagarine (4), oxyberberine (5), canthin-6-one (6), 4-methoxy-N-methyl-2-quinolone (7) and oxypalmatine (8) based on the physicochemical and spectroscopic data. Compounds 3, 5, 7, and 8 were first isolated from the Phellodendron amurense. The isolated compounds were then tested for their cytotoxicity against five human tumor cell lines in vitro using the SRB method. Compound 5 showed significant cytotoxicity against the five tumor cell lines with ED50 values ranging from 0.30 to 3.0 microg/mL. The marginal or noncytotoxic compounds (1, 2, 3, 4, and 7) were examined for their P-gp related MDR reversal activities. Compound 1 showed significant P-gp MDR inhibition activity in MES-SA/DX5 and HCT15 cells with an ED50 value of 0.028 microg/mL and 0.0011 microg/mL, respectively.     

The medicinal chemistry of multidrug resistance (MDR) reversing drugs

Multidrug resistance (MDR) is a kind of resistance of cancer cells to multiple classes of chemotherapic drugs that can be structurally and mechanistically unrelated. Classical MDR regards altered membrane transport that results in lower cell concentrations of cytotoxic drug and is related to the over expression of a variety of proteins that act as ATP-dependent extrusion pumps. P-glycoprotein (Pgp) and multidrug resistance protein (MRP1) are the most important and widely studied members of the family that belongs to the ABC superfamily of transporters. It is apparent that, besides their role in cancer cell resistance, these proteins have multiple physiological functions as well, since they are expressed also in many important non-tumoural tissues and are largely present in prokaryotic organisms. A number of drugs have been identified which are able to reverse the effects of Pgp, MRPI and sister proteins, on multidrug resistance. The first MDR modulators discovered and studied in clinical trials were endowed with definite pharmacological actions so that the doses required to overcome MDR were associated with unacceptably high side effects. As a consequence, much attention has been focused on developing more potent and selective modulators with proper potency, selectivity and pharmacokinetics that can be used at lower doses. Several novel MDR reversing agents (also known as chemosensitisers) are currently undergoing clinical evaluation for the treatment of resistant tumours. This review is concerned with the medicinal chemistry of MDR reversers, with particular attention to the drugs that are presently in development.     

Aporphine alkaloids from <Emphasis Type="Italic">Clematis parviloba</Emphasis> and their antifungal activity

A new aporphine alkaloid, β-magnoflorine (1), together with a known aporphine alkaloid, α-magnoflorine (2), were isolated from the aerial parts of Clematis parviloba. Their structures were elucidated on the basis of comprehensive spectroscopic techniques. In addition, both compounds showed potent antifungal activities against Penicillium avellaneum UC-4376.     

Jacaranone and related compounds from the fresh fruits ofTernstroemia japonica and their antioxidative activity

Jacaranone and related compounds (1-3) were isolated, along with three triterpenes (4-6), from the fresh fruits of Ternstroemia japonica. The compounds were identified as jacaranone (1), 3-hydroxy-2,3-dihydrojacaranone (2), 3-methoxy-2,3-dihydrojacaranone (3), 3-O-acetyloleanolic acid (4), 3-O-acetylursolic acid (5), and ursolic acid (6). Jacaranone and its derivatives were isolated for the first time from Theaceae. Of the isolated compounds, compound 3 is a new compound. Jacaranone (1) exhibited weak antioxidative effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical.     

Norditerpenoid alkaloids and other components from the processed tubers ofaconitum carmichaeli

A new norditerpenoid and a known alkaloid were isolated from the alkaloidal fraction of the processed tubers of Aconitum carmichaeli. The structure of the new norditerpenoid alkaloid was elucidated as lipoforesaconitine (1) on the basis of spectroscopic analysis. The known norditerpenoid alkaloid was characterized as lipoyunanaconitine (2). In addition, a new flavonoid, 6"-O-acetylliquiritin (7), along with a known ceramide, (2S,3S,4R,8E)-2-[(2'R)-2'-hydroxylignoceroylamino]-8(E)-octadecene-1,3,4-triol (3), as well as a known steroid saponin, gracillin (8), and three known flavonoids, liquiritigenin (4), isoliquiritigenin (5), and liquiritin (6), were also isolated and characterized. All known compounds were isolated from this plant for the first time. The structures of the isolates were established by spectroscopic and chemical methods.     

Norditerpenoid and dianthramide glucoside alkaloids from cultivated<Emphasis Type="Italic">aconitum</Emphasis> species from Korea

A new norditerpene alkaloid named 8-O-methylhypaconine (1) was isolated along with twelve known alkaloids from the underground parts of an unknown species of Aconitum plant culti vated in Korea. Among the known alkaloids, two dianthramide glucosides, N-(2'-beta-glucopyra nosyl-5'-hydroxysalicyl)-5-hydroxyanthranilic acid methyl ester (2) and N-(2'-beta-glucopyranosyl-5'-hydroxysalicyl)-5-hydroxy-6-methoxyanthranilic acid methyl ester (3), were isolated from Aconitum plants for the first time. The structures were established on the basis of chemical and spectroscopic methods.     

mdr1及P-gp与脑胶质瘤耐药关系的研究

恶性胶质瘤患者平均生存期较短,通常手术切除肿瘤组织并不能从根本上延长患者的生存时间,而且应用药物化疗易产生多药耐药性(multidrug resistance,MDR),使化疗失败。P-糖蛋白(P-glycoprotein,P-gp)和多药耐药相关蛋白(multidrug resistance associated protein,MRP)介导的药物外排是产生MDR的主要机制,其编码基因分别为mdr1和     

白蔹的化学成分

目的研究白蔹的化学成分。方法利用各种色谱法进行分离,根据理化性质和波谱数据鉴定结构。结果从白蔹的乙酸乙酯萃取液中分离得到8个已知成分,分别鉴定为没食子酸(1)、原儿茶酸(2)、龙胆酸(3)、白藜芦醇(4)、大黄素(5)、羽扇豆醇(6)、β-谷甾醇(7)、胡萝卜苷(8)。结论化合物2和3为从该植物中首次分离得到。     

Mycosynthesis,characterization and antibacterial properties of AgNPs against multidrug resistant (MDR) bacterial pathogens of female infertility cases

Recently, biosynthesis of silver nanoparticles using bacteria, fungus and plants has emerged as a simple and viable alternative to more complex physical and chemical synthetic procedures. The present investigation explains rapid and extracellular synthesis of silver nanoparticles using fungus Fusarium oxysporum NGD and characterization of the synthesized silver nanoparticles using UV-Vis spectroscopy, scanning electron microscopy, energy dispersive spectroscopy and X-ray diffraction analysis. The size range of the synthesized silver nanoparticles was around 16.3–70 nm. The FTIR studies showed major peaks of proteins involved in the synthesis of silver nanoparticles. Further, antibacterial effect of the silver nanoparticles against multidrug resistant pathogens Enterobacter sp. ANT 02 [HM803168], Pseudomonas aeruginosa ANT 04 [HM803170], Klebsiella pneumoniae ANT 03 [HM803169] and Escherichia coli ANT 01 [HM803167] was tested using turbidometric assay at 10, 20, 30, 40 μg AgNPs/ml alone and in combination with ampicillin using agar well diffusion assay. All the resistant bacteria were found to be susceptible to the antibiotic in the presence of the silver nanoparticles.     

Anti-platelet effects of flavonoids and flavonoid-glycosides from Sophora japonica

A methanol extract of Sophora japonica was subjected to anti-platelet activity guided fractionation affording the isolation of four flavonoids and six flavonoid-glycosides: biochanin A (1), irisolidone (2), genistein (3), sissotrin (4), sophorabioside (5), genistin (6), tectoridin (7), apigenin (8), quercitrin (9), and rutin (10). The structure of each compound was determined by a variety of spectroscopic methods. Among the compounds, 1, 3, and 7 showed approximately 2.5-6.5 fold greater inhibitory effects on arachidonic acid (AA) and U46619 induced platelet aggregation (IC50: 19.9 and 99.8 microM; 20.3 and 53.8 microM; 25.9 and 123.4 microM, respectively) than acetylsalicylic acid (ASA, IC50: 63.0 and 350.0 microM). Compound 2 was an approximately 22-40 fold stronger inhibitor than ASA on AA and U46619 induced aggregation (IC50: 1.6 and 15.6 microM, respectively).     

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.     

Antioxidant flavonoids and chlorogenic acid from the leaves ofEriobotrya japonica

The antioxidant activity of Eriobotrya japonica was determined by measuring the radical scavenging effect on DPPH (1,1-diphenyl-2-picrylhydrazyl) radical and lipid peroxidation produced when mouse liver homogenate was exposed to the air at 37 degrees C, using 2-thiobarbituric acid (TBA). The methanol extract and its fractions of Eriobotrya japonica leaves showed strong antioxidant activity. The antioxidant activity of EtOAc and n-BuOH soluble fractions were stronger than the others, and were further purified by repeated silica gel, MCl gel CHP-20P, and Sephadex LH-20 column chromatography. Antioxidant chlorogenic acid, quercetin-3-sambubioside from n-BuOH fraction, and methyl chlorogenate, kaempferol- and quercetin-3-rhamnosides, together with the inactive ursolic acid and 2 alpha-hydroxyursolic acid from EtOAc fraction were isolated. Antioxidant flavonoids and chlorogenic acid also showed prominent inhibitory activity against free radical generation in dichlorofluorescein (DCF) method.     

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.     

Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes

One of the major obstacles to the success of cancer chemotherapy is the multidrug resistance (MDR) often resulting due to the overexpression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results in overcoming the MDR. However, P-gp is also expressed in normal tissues like blood brain barrier, gastrointestinal track, liver, spleen and kidney. To maximize the efficacy of P-gp inhibitor and reduce the systemic toxicity, it is important to limit the exposure of P-gp inhibitors and the anticancer drugs to normal tissues and increase their co-localization with tumor cells. In this study, we have investigated the co-delivery of the P-gp inhibitor, tariquidar, and cytotoxic drug, paclitaxel, into tumor cells to reverse the MDR using long-circulating liposomes. Tariquidar- and paclitaxel-loaded long-circulating liposomes showed significant resensitization of the resistant variant for paclitaxel, which could be correlated with an increased accumulation of paclitaxel in tumor cells. These results suggest that the co-delivery of the P-gp inhibitor, tariquidar, and the cytotoxicity inducer, paclitaxel, looks like a promising approach to overcome the MDR.     

Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase

As part of our ongoing search of natural sources for therapeutic and preventive agents for diabetic complications, the rat lens aldose reductase (RLAR) inhibitory effect of Coptidis Rhizoma (the rhizome of Coptis chinensis Franch) was evaluated. Its extract and fractions exhibited broad and moderate RLAR inhibitory activities of 38.9∼67.5 μg/mL. In an attempt to identify bioactive components, six quaternary protoberberine-type alkaloids (berberine, palmatine, jateorrhizine, epiberberine, coptisine, and groenlandicine) and one quaternary aporphine-type alkaloid (magnoflorine) were isolated from the most active n-BuOH fraction, and the chemical structures therein were elucidated on the basis of spectroscopic evidence and comparison with published data. The anti-diabetic complications capacities of seven C. chinensis-derived alkaloids were evaluated via RLAR and human recombinant AR (HRAR) inhibitory assays. Although berberine and palmatine were previously reported as prime contributors to AR inhibition, these two major components exhibited no AR inhibitory effects at a higher concentration of 50 μg/ml in the present study. Conversely, epiberberine, coptisine, and groenlandicine exhibited moderate inhibitory effects with IC₅₀ values of 100.1, 118.4, 140.1 μM for RLAR and 168.1, 187.3, 154.2 μM for HRAR. The results clearly indicated that the presence of the dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring were partly responsible for the AR inhibitory activities of protoberberine-type alkaloids. Therefore, Coptidis Rhizoma, and the alkaloids contained therein, would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.     

Geographically-based evaluation of multidrug resistance trends among Streptococcus pneumoniae in the USA: findings of the FAST surveillance initiative (2003-2004)

Surveillance initiatives to track Streptococcus pneumoniae resistance trends are important for understanding the current in vitro effectiveness of available antimicrobial agents. The antimicrobial susceptibility profiles of S. pneumoniae (n = 1479 isolates) collected from 17 geographical areas across the USA (2003–2004) were analysed; 36.8% of isolates were resistant to one or more agents (24.4% were multidrug-resistant, i.e. resistant to two or more antimicrobial classes). Multidrug resistance involved resistance to β-lactams, macrolides, tetracycline and trimethoprim/sulphamethoxazole, but rarely fluoroquinolones (>96% of multidrug-resistant isolates were fluoroquinolone-susceptible). Multidrug resistance rates were prominent regardless of the geographical region surveyed. As this trend continues, the empirical therapeutic options for S. pneumoniae infections will diminish and there will be an ongoing need to evaluate the effectiveness of potent fluoroquinolones such as gemifloxacin.     

胡蔓藤生物碱的化学研究 Ⅱ.胡蔓藤碱丙(humantenidine)的化学结构

自马钱科(Loganiaceae)植物胡蔓藤(Gelsemium elegans Benth.)根的生物碱提取物中分离得到的一个新的氧化吲哚生物碱,命名为胡蔓藤碱丙(humantenidine),经光谱(UV,IR,¹HNMR,¹³CNMR,MS)分析和衍生物的制备,确定其化学结构为式(Ⅰ)所示