大青叶和板蓝根药材及其制剂质量控制的研究

首次提出以2,4(1H,3H)喹唑二酮[2,4(1H,3H)quinazolinedione]作为马蓝、蓼蓝药材及其制剂的质量控制指标。此成分系最近发现的,含量稳定且有代表性,尤其适用于评价此类中药制剂的真伪优劣,为当前难以解决的感冒退热冲剂和板蓝根冲剂的质量监控提供了可靠的方法。特别要指出的是本文是在高效液相色谱法中采用变换检测波长和梯度洗脱的方法,一次进样即可完成三种化学性质不同组分的含量分析,缩短了分析时间,提高了分析效率。     

7-甲氧基-4-(2-甲基-4-喹唑啉基)-3,4-二氢喹噁啉-2(1H)-酮的合成工艺改进

目的:改进7-甲氧基-4-(2-甲基-4-喹唑啉基)-3,4-二氢喹噁啉-2(1H)-酮的合成工艺。方法:以2-甲基-4(3H)-喹唑啉酮为起始原料,通过氯代、亲核取代、二芳胺烷基化和硝基还原环合等反应对7-甲氧基-4-(2-甲基-4-喹唑啉基)-3,4-二氢喹噁啉-2(1H)-酮的合成工艺进行改进,并考察其收率。结果:7-甲氧基-4-(2-甲基-4-喹唑啉基)-3,4-二氢喹噁啉-2(1H)-酮的结构经核磁共振氢谱和电喷雾质谱确证,总收率为43.5%,较改进前的20.2%提高了23.3%。结论:改进后的工艺更简单,条件更温和,适合实验室研究的批量制备。     

(S)-5-(氮杂环亚甲基)-3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮衍生物的合成及抗菌活性

目的研究具有抗菌作用的噁唑烷酮衍生物的构效关系。方法由(S)-[3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮-5-基]-甲醇甲磺酸酯和仲胺的取代反应合成了7个(S)-5-氮杂环亚甲基-3-(3-氟-4-吗啉-4-基-苯基)噁唑烷-2-酮衍生物,其结构通过1HNMR和元素分析或质谱确证。结果所合成的7个化合物对所测的20株细菌均没有明显的体外抗菌活性。结论用氮杂环亚甲基取代吗啉噁酮的5位乙酰胺甲基降低化合物的抗菌活性。     

阿立哌唑的合成工艺

目的　考察阿立哌唑的合成路线。方法　以7-羟基- 3,4 -二氢- 2 (1H) -喹喏酮为原料,经O -溴丁基化和缩合反应合成阿立哌唑。结果　阿立哌唑总收率为81%,经元素分析、红外光谱确证化学结构正确。结论　该合成路线适于工业化生产。     

氟喹酮类:结构、作用和耐药机理、体外抗菌谱

过去的5～7年中人们把更多的注意力集中于新的4-喹诺酮药物的合成及评价上,因而发现了许多6-氟7-哌嗪-4-喹酮(6-fluoro-7-piperazino-4-quinolones)类药物。这些药物对革蓝氏阴性杆菌和球菌的体外抗菌活性的广度和强度以及口服能耐受剂量即可控制由实验性细菌引起的全身性感染的能力皆值得注意。其中活性最强的代表药物是氟哌酸(norfloxacin Bay 09867)、氨氟哌酸(amifloxacin,Win 49375)、氟啶酸(enoxacin,AT-2266,CI-919)以及甲氟哌酸(pefloxacin,1589-RB)等氟喹酮类药物。     

恩诺沙星噁二唑硫酮曼尼希衍生物的合成及抗肿瘤活性

目的为发现氟喹诺酮C-3羧基等排体的优化方法。方法用噁二唑硫酮杂环替代恩诺沙星(1)C-3羧基,以曼尼希碱作为修饰侧链,设计合成了10个新的恩诺沙星C-3羧基等排体——噁二唑硫酮曼尼希碱目标化合物(4a-4j),其结构经元素分析和光谱数据确证。用MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐)方法评价了目标化合物体外对SMMC-7721、L1210和HL60 3种癌细胞的生长抑制活性。结果目标物对3种实验癌细胞的生长抑制活性强于母体化合物1和中间体噁二唑酮3的活性,其中以哌嗪和对氟苯胺为胺供体目标化合物对SMMC-7721细胞的活性高于其他胺供体化合物的活性,其活性与对照阿霉素的活性相当。结论噁二唑硫酮杂环可作为氟喹诺酮C-3羧基的等排体,用曼尼希碱侧链修饰可显著提高其抗肿瘤活性。     

新药工艺介绍

ND-022 氯唑沙宗(Chlorzoxazone)5-氯-2(3H)-苯并(口恶)唑酮C7H4CINO2(169.6)mp191～191.5℃     

7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物的合成与抗菌活性

目的寻找新型的噁唑烷酮-氟喹诺酮类抗菌药物。方法设计合成了7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物，测定其体外抗菌活性。结果共合成20个目标化合物，经^{1H NMR和MS确证结构。目标化合物具有较好的体外抗菌活性，尤其是化合物22，对屎肠球菌的抑制活性分别是吗啉噁酮和诺氟沙星的16倍和64倍，对金葡菌的抑制活性为吗啉噁酮的4倍。结论某些带有氟喹诺酮结构片段的噁唑烷酮类化合物抗菌活性加强。}     

季胺化4(3H)-喹唑啉酮类的药理学研究

早期的研究结果表明,喹唑啉酮类的主要生理活性有:镇静,催眠,抗痉挛,肌肉松弛,止痛和抗菌作用.其中大多数作用都涉及到了中枢神经系统.例如,其强效衍生物安眠酮,除具有催眠作用外,还有显著的抗戊四唑(PTz)诱发性痉挛作用.然而,它同时也无法避兔许多严重的副作用.一般认为副作用与亲脂性的喹唑啉酮环有关.因此,我们以2-甲基-3-氯乙酰氨基-4(3H)-喹唑啉酮与一些芳香胺作用,使吡啶环上的氮季胺化,产生亲水性更强的2-甲基-3-(取代吡啶)乙酰氨基-4(3H)-喹唑啉酮盐酸盐,以提高活性,同时降低副作用.     

新非甾体镇痛消炎药:4-二氧基-2-甲基-5-吗啉-3(2H)哒嗪酮及有关化合物

在研究哒嗪酮衍生物的构-效关系过程中,作者以3(2H)-哒嗪酮骨架为基础,通过变换功能基位置,对B型结构进行改造;讨论了4-烷氧基-2-取代-5-(取代氨基)3(2H)-哒嗪酮地(C)的合成和镇痛消炎的构-效关系,并发现4-乙氧基-2-甲基-5-吗啉-3(2H)哒嗪酮(8)活性显著,有可能用于临床。     

马蓝的化学成分研究

Seven compounds have been isolated from the whole plant of Strobilanthes cusia (Nees) O. Ktze. Three of them are triterpenes (Ⅰ～Ⅲ), two are indole alkaloids (Ⅳ, Ⅴ), two are quinazolinone alkaloids (Ⅵ, Ⅶ). On the basis of spectral analysis and physicochemical properties, their structures were established as lupeol (Ⅰ), betulin (Ⅱ), lupenone (Ⅲ), indigo (Ⅳ), indirubin (Ⅴ), 4 (3H)-quinazolinone (Ⅵ), 2, 4 (1H, 3H)-quinazolinedione (Ⅶ). Ⅵ and Ⅶ were found from natural plant for the first time.The results of the pharmacological tests demonstrate that compound Ⅴ has anticancer activity and compound Ⅵ has hypotensive action. Compound Ⅶ can be quantitatively determined by HPLC, which may serve as a quality control standard for materia medica and its preparations. Compounds Ⅵ and Ⅶ have been confirmed by means of synthesis.     

中药红泽兰化学成分的研究

本文报道从中药红泽兰(爵床科马兰属植物垂序马兰StrobilanShes japonicusⅠ的全草)中分离出的黄酮和甾醇四种成分。经化学及光谱分析鉴定其中之一为新黄酮甙(Ⅱ),命名为红泽兰甙(strobilanthin),即5,7-二甲氧基-4′-羟基黄酮-4’-0-芹糖甙;另一系首次直接从天然界中分得的黄酮化合物(Ⅰ),为前者的甙元即5,7-二甲氧基-4’-羟基黄酮;其余两种均首次从马兰属植物中分出,分别为豆甾醇(Ⅲ)和豆甾-8(14)-烯-3-醇(Ⅳ)。     

Didanosine (ddI) and zidovudine (ZDV) susceptibilities of human immunodeficiency virus (HIV) isolates from long-term recipients of ddI

Thirty HIV isolates, obtained from 15 patients before and after receiving single drug therapy with didanosine (ddI), were examined for sensitivity to ddI and zidovudine (ZDV) using a peripheral blood mononuclear leukocyte (PBML)-based assay. Fourteen of the patients had ARC, one had AIDS and 12 had received previous therapy with ZDV. After a median of 1 year of ddI therapy, isolates were significantly less sensitive to ddI than were isolates obtained prior to therapy (P = 0.03). A decrease in ddI sensitivity was observed in ten of the 15 isolate pairs. In contrast to ddI susceptibilities, sensitivity to ZDV increased over the same period of time (P = 0.03). Additional isolates were obtained from four patients who received ddI monotherapy for 2 years. Three of these isolates demonstrated no change in ddI sensitivity compared to baseline. No correlation could be made in this study between development of decreased ddI sensitivity and serum p24 levels, CD4 counts, or clinical outcome. Decreased ddI sensitivity occurs frequently among HIV isolates obtained from long-term recipients of ddI. This decreased sensitivity is modest in degree and is of unknown clinical significance.     

Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy

Breast cancer is one of the most common types of cancer in female patients with high morbidity and mortality. Multi-drug chemotherapy has significant advantages in the treatment of malignant tumors, especially in reducing drug toxicity, increasing drug sensitivity and reducing drug resistance. The objective of this research is to fabricate lipid nanoemulsions (LNs) for the co-delivery of PTX and docosahexaenoic acid (DHA) with folic acid (FA) decorating (PTX/DHA-FA-LNs), and investigate the anti-tumor activity of the PTX/DHA-FA-LNs against breast cancer both in vitro and in vivo. PTX/DHA-FA-LNs showed a steady release of PTX and DHA from the drug delivery system (DDS) without any burst effect. Furthermore, the PTX/DHA-FA-LNs exhibited a dose-dependent cytotoxicity and a higher rate of apoptosis as compared with the other groups in MCF-7 cells. The cellular uptake study revealed that this LNs were more readily uptaken by MCF-7 cells and M2 macrophages in vitro. Additionally, the targeted effect of PTX/DHA-FA-LNs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. The anti-tumor efficiency results showed that PTX/DHA-FA-LNs significant inhibited tumor volume growth, prolonged survival time, and reduced toxicity when compared with the other groups. These results indicated that DHA increases the sensitivity of tumor cells and tumor-associated macrophages (ATM2) to PTX, and synergistic effects of folate modification in breast cancer treatment, thus PTX/DHA-FA-LNs may be a promising nanocarrier for breast cancer treatment.     

Clonazepam release from core-shell type nanoparticles of poly(-caprolactone)/poly(ethylene glycol)/poly(-caprolactone) triblock copolymers

The triblock copolymer based on poly(-caprolactone) (PCL) as hydrophobic part and poly(ethylene glycol) (PEG) as hydrophilic one was synthesized and characterized. Core-shell type nanoparticles of poly(-caprolactone)/poly(ethylene glycol)/poly(-caprolactone) (CEC) block copolymer were prepared by a dialysis technique. According to the amphiphilic characters, CEC block copolymer can self-associate at certain concentration and their critical association concentration (CAC) was determined by fluorescence probe technique. CAC value of the CEC-2 block copolymer was evaluated as 0.0030 g/l. CAC values of CEC block copolymer decreased with the increase of PCL chain length, i.e. the shorter the PCL chain length, the higher the CAC values. From the observation of transmission electron microscopy (TEM), the morphologies of CEC-2 core-shell type nanoparticles were spherical shapes. Particle size of CEC-2 nanoparticles was 32.3±17.3 nm as a monomodal and narrow distribution. Particle size, drug loading, and drug release rate of CEC-2 nanoparticles were changed by the initial solvents and the molecular weight of CEC. The degradation behavior of CEC-2 nanoparticles was observed by ¹H NMR spectroscopy. It was suggested that clonazepam (CNZ) release kinetics were dominantly governed by diffusion mechanism.     

Pharmacological characterization of a selective COX-2 inhibitor MF-tricyclic, [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], in multiple preclinical species

Selective type 2 cyclooxygenase (COX-2) inhibitors are often used in preclinical studies without potency and selectivity data in the experimental species. To address this issue, we assessed a selective COX-2 inhibitor MF-tricyclic in four commonly used species, namely mice, rats, guinea pigs and rabbits, in the present study. In both the guinea pig and rabbit whole blood assay, the compound inhibited lipopolysaccharide (LPS)-induced PGE₂ production with an IC₅₀ (COX-2) of 0.6 and 2.8 μM, respectively. By comparison, the compound displayed a much weaker activity on clot-induced formation of thromboxane with an IC₅₀ (COX-1) of > 10 μM (guinea pigs) and 23 μM (rabbits). In keeping with the in vitro potency data, the compound significantly inhibited interleukin-1 beta (IL-1β) -induced PGE₂ formation in the rabbit synovium at plasma concentrations near the whole blood assay IC₅₀ for COX-2 but much lower than that for COX-1. MF-tricyclic was also potent and selective toward COX-2 in mice, inhibiting carrageenan-induced PGE₂ accumulation in the air pouch dose-dependently (ED₅₀ = 0.5 mg/kg) without affecting stomach PGE₂ levels. In rats, MF-tricyclic was found to be effective in three standard in vivo assays utilized for assessing COX-2 inhibitors, namely, LPS-induced pyresis, carrageenan-induced paw edema and adjuvant-induced arthritis at the doses that did not inhibit stomach PGE₂ levels. Similar to that in rats, the compound displayed pharmacological efficacy in mice, guinea pigs and rabbits when tested in the LPS pyresis model. Our data reveal that MF-tricyclic has the desired biochemical and pharmacological properties for selective COX-2 inhibition in all four test species.     

TSPO 18 kDa (PBR) Targeted Photosensitizers for Cancer Imaging (PET) and PDT

相似文献   

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

相似文献   

不同表面活性剂修饰的汉防己甲素PLGA纳米粒制备表征及体外评价

目的:基于纳米粒的递送系统,以改善天然化合物汉防己甲素对肺癌的功效。方法:选取聚乙烯醇、普朗尼克-F127和双十二烷基二甲基溴化铵3种不同的稳定剂,采用单乳化扩散溶剂挥发法制备载汉防己甲素的PLGA纳米粒,考察不同稳定剂对载药纳米粒粒径、ζ电位以及对肺癌A549细胞摄取的影响。结果:2%,1%和0.1%浓度的PVA、PF127和DMAB制备的纳米粒呈表面光滑、大小均一的球形,粒径范围均控制在180~200nm;药物包封率为50%~60%;体外释放实验显示,在pH 7.4的PBS溶液中3组载药纳米粒均呈现缓慢持续释药;细胞学实验结果表明3组纳米粒给药系统均表现出比药物更强的抗肿瘤活性。结论:对PLGA进行表面修饰制备的纳米载体能使汉防己甲素的给药效率得到明显提升。     

Pharmacokinetics and bioactivity of glial cell line-derived factor (GDNF) and neurturin (NTN) infused into the rat brain

Convection-enhanced delivery (CED) of GDNF and NTN was employed to determine the tissue clearance of these factors from the rat striatum and the response of the dopaminergic system to a single infusion. Two doses of GDNF (15 and 3 μg) and NTN (10 μg and 2 μg) were infused into the rat striatum. Animals were euthanized 3, 7, 14, 21, and 28 days post-infusion. Brains were processed for ELISA, HPLC, and immunohistochemistry (IHC). Both doses of the infused GDNF resulted in a sharp increase in striatal GDNF levels followed by a rapid decrease between day 3 and 7. Interestingly, IHC revealed GDNF in the septum and the base of the brain 14 days after GDNF administration. Dopamine (DA) turnover was significantly increased in a dose-dependent manner for more than 7 days after a single GDNF infusion. NTN persisted in the brain for at least two weeks longer than GDNF. It also had more persistent effects on DA turnover, probably due to its precipitation in the brain at neutral pH after infusion. Our data suggest that daily or continuous dosing may not be necessary for delivering growth factors into the CNS.