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.     

顶空气相色谱法检测他达拉非原料药中4种溶剂残留量

目的建立测定他达拉非原料药中4种常见溶剂(甲醇、乙腈、异丙醇、四氢呋喃)残留量的顶空气相色谱法。方法采用顶空进样方式,分离柱采用DB-624柱(30 m×0.53 mm,3.0μm),程序升温,进样口温度为230℃,分流比为5∶1,载气为高纯氮气(纯度为99.999%),载气流速为1.8 mL/min;采用氢火焰离子化检测器检测,检测器温度为250℃。外标法定量。结果甲醇、乙腈、异丙醇、四氢呋喃的质量浓度线性范围分别为0.66~1.5 mg/mL,0.0082~0.205 mg/mL,0.06~1.5 mg/mL,0.0144~0.36 mg/mL;平均加样回收率分别为101.22%,100.59%,97.74%,100.73%,RSD分别为4.67%,2.63%,1.01%,2.28%(n=6);检测限分别为2μg/mL,8μg/mL,5μg/mL,6μg/mL。结论该方法操作简单,灵敏度高,准确性好,为可他达拉非中有机溶剂残留量的控制提供依据。     

Neuroprotective effect of gold nanoparticles composites in Parkinson's disease model

Parkinson’s disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo.     

顶空气相色谱法测定米非司酮中有机残留溶剂含量

目的建立米非司酮中残留有机溶剂的检测方法。方法采用顶空进样毛细管气相色谱法.以为1%的盐酸水为溶解介质,色谱柱为DB-Waxetr PEG2000,载气为氮气,FID检测器,测定米非司酮中残留的丙酮、二氯甲烷、异丙醚、四氢呋喃、环己烷。结果溶媒对残留溶剂测定无干扰,线性关系良好。结论顶空气相色谱法测定米非司酮中残留溶剂分离效果好,方法灵敏、准确。     

Identification, quantitation and biological activity of phytoestrogens in a dietary supplement for breast enhancement

A hop-based dietary supplement, marketed for natural breast enhancement, was analysed to determine the identity and biological activity of active constituents and potential biological effects in man. Extracts of the dietary supplement were analysed by LC-MS(n) and phytoestrogens identified and quantitated by reference to appropriate standards. Only hop-associated phytoestrogens were found in the dietary supplement at significant concentrations as follows (mean+/-1 S.D.); 8-prenylnaringenin 10.9+/-0.3, 6-prenylnaringenin 27.4+/-1.2, 6,8-diprenylnaringenin 0.9+/-0.1, xanthohumol 321+/-17 and isoxanthohumol 81.1+/-1.6 microg/g of dietary supplement. The oestrogenic activity of extracts in an ERalpha reporter gene assay was equivalent to 48+/-6.3 ng 17beta-oestradiol/g supplement and consistent with the 8-prenylnaringenin content. The dietary supplement extract also inhibited reductive 17beta-hydroxysteroid oxidoreductase activity, but to a greater extent than a concentration matched reference mixture of hop phytoestrogens. However, the supplement was only weakly active in mouse uterotrophic assays following administration in feed or after subcutaneous injection of extract at doses of 8-PN up to 250 times higher than that recommended for women. These preliminary findings suggest that the dietary supplement is unlikely to produce oestrogenic effects in vivo at the level of the uterus; supporting evidence is still required to demonstrate efficacy.     

Safety assessment of a novel ingredient for removable chewing gum

Rev7™ is an indigestible gum polymer used for the manufacturing of chewing gum. It allows for the formulation of chewing gum with low adhesion; thus can be readily removed from surfaces such as sidewalks, clothing, carpets and furniture. In a toxicological safety assessment, Rev7™ was found to be non-mutagenic in the AMES assay. The highest concentration tested in a mouse lymphoma thymidine kinase locus gene mutation assay induced a slight but biologically relevant increase in mutations under non-metabolic activation conditions after 24 h. Because of this finding, a mouse micronucleus assay was performed, and the test article was found to be negative for inducing chromosomal damage. A 28-day repeated oral toxicity study resulted in a NOAEL of 80,000 ppm; the highest concentration tested. Rev7™ was found to be free from contaminants such as heavy metals, monomers, and solvents. Lastly, Rev7™ did not demonstrate skin-sensitizing properties in the murine local lymph node assay.     

Data mining of NCI's anticancer screening database reveals mitochondrial complex I inhibitors cytotoxic to leukemia cell lines

Mitochondria are principal mediators of apoptosis and thus can be considered molecular targets for new chemotherapeutic agents in the treatment of cancer. Inhibitors of mitochondrial complex I of the electron transport chain have been shown to induce apoptosis and exhibit antitumor activity. In an effort to find novel complex I inhibitors which exhibited anticancer activity in the NCI's tumor cell line screen, we examined organized tumor cytotoxicity screening data available as SOM (self-organized maps) (http://www.spheroid.ncifcrf.gov) at the developmental therapeutics program (DTP) of the National Cancer Institute (NCI). Our analysis focused on an SOM cluster comprised of compounds which included a number of known mitochondrial complex I (NADH:CoQ oxidoreductase) inhibitors. From these clusters 10 compounds whose mechanism of action was unknown were tested for inhibition of complex I activity in bovine heart sub-mitochondrial particles (SMP) resulting in the discovery that 5 of the 10 compounds demonstrated significant inhibition with IC50's in the nM range for three of the five. Examination of screening profiles of the five inhibitors toward the NCI's tumor cell lines revealed that they were cytotoxic to the leukemia subpanel (particularly K562 cells). Oxygen consumption experiments with permeabilized K562 cells revealed that the five most active compounds inhibited complex I activity in these cells in the same rank order and similar potency as determined with bovine heart SMP. Our findings thus fortify the appeal of mitochondrial complex I as a possible anticancer molecular target and provide a data mining strategy for selecting candidate inhibitors for further testing.     

Extraction de l’artémisinine et synthèse de ses dérivés: artésunate et artéméther

Artemisinin is extracted from a shrub called sweet wormwood, or Artemisia annua, and has been used in China for more than 1500 years for clinical purposes. Based on its potential medicinal properties, more and more investigations have been carried out, and mounting evidence suggests that this compound may be effective in the treatment of malaria. Moreover, the observation that the malaria parasite is developing increasing resistance to the majority of antimalarial drugs has raised the possibility that artemisinin could play an indispensable role in controlling the disease. Although artemisinin seems very promising, it remains expensive, which limits its accessibility. In the present report, we discuss the development of a simple and cost-effective method to extract, synthesize and purify artemisinin and its derivatives, in an effort to take part in the global fight against malaria. The use of the solvent dichloromethane offers a number of advantages: it is non-explosive, easier to manipulate, and can consequently be transferred without risk to the Artemisia annua culture site, where extraction takes place. This avoids the transport of large volumes of leaves to the laboratory, an expensive process that requires a special storage area. In addition, the evaporation and recovery of the solvent are relatively less demanding, making it possible to recover and reuse it for further extractions; this results in significantly lower costs as well as reduced dichloromethane transport needs. Finally, this extraction method avoids the transport of large volumes of leaves to the laboratory. We conclude that this method represents a low-cost technique that can be adapted to any pharmaceutical laboratory with relative ease, especially in developing countries.     

车间空气中呋喃和四氢呋喃的气相色谱测定法

本文建立了用活性炭管采样,热解吸,气相色谱测定车间空气中呋喃和四氢呋喃浓度的方法。采用内装100mg活性炭的采样管,在0.5mg/m~3呋喃和300mg/m~3四氢呋喃,空气湿度为89％时,以0.1L/min速度采样,呋喃和四氢呋喃的穿透容量分别为2.64mg和9.36mg。在温度250℃,氮气流量1ml/s下,四种浓度水平的解吸效率均大于92％。样品于室温下在活性炭管中贮存一周无明显丢失。气相色谱测定呋喃和四氢呋喃的最低检测限分别为1.0×10~(-4)μg和2.3×10~(-3)μg(进1.0ml空气样品),变异系数小于5％。     

聚氧四甲撑二醇的合成研究：发烟硫酸法PTMG的合成

对以发烟硫酸为主体的双元催化剂进行四氢呋喃开环聚合剂制备聚氧甲甲撑二醇进行了系统的研究。实验结果表明开环聚合宜采用３０％浓度的发烟硫酸，通过正交实验得到了聚合反应的最佳条件；辅助催化剂Ｂ的加入可灵活调整产品的数均分子量；未反应的四氢呋喃经适当处理后可以回收循环使用。