川芎嗪代谢物糖酯衍生物的合成及生物活性

针对川芎嗪在体内易代谢、作用时间过短等问题,通过KMnO_4氧化川芎嗪法制备了其活性代谢物3,5,6-三甲基吡嗪甲酸,并与5种溴代糖缩合合成了不同的糖酯,有关中间体和目标化合物的结构均经过IR、~1HNMR和MS确证;在此基础上考察了5种糖酯衍生物的抗凝血和抗急性缺氧活性,结果表明,给药1h后川芎嗪和糖酯衍生物抗凝血和抗急性缺氧效果差距不大,但给药3h后的糖酯衍生物仍有较好的抗凝血和抗急性缺氧活性能力,这也表明新合成的几种川芎嗪糖酯类衍生物有效地减缓了川芎嗪在体内的代谢速度、延长了体内作用时间。     

川芎嗪芳酸衍生物的合成及抗血小板聚集活性

以具有活血化淤作用的中药有效成分川芎嗪、阿魏酸为先导物, 按药物化学拼合原理, 设计合成了6个全新结构的川芎嗪芳酸衍生物, 其结构经IR, 1H NMR, 13C NMR及MS确证. 体外药效筛选结果显示, 部分川芎嗪芳酸衍生物对二磷酸腺苷(ADP)诱导的血小板聚集具有较好的抑制活性, 其中川芎嗪阿魏酸拼合物(1a)的抑制活性是奥扎格雷的5.7倍.     

新型川芎嗪阿魏酸衍生物的合成及其抗血小板聚集活性

以阿魏酸及其类似物为原料,设计并合成了6个新型的川芎嗪阿魏酸衍生物,其结构经1H NMR,13C NMR,IR及MS表征.初步药理活性测试结果显示,部分化合物的血小板抑制率较高.     

新型川芎嗪衍生物的合成

以川芎嗪为原料，经氧化、Boekelheide重排、水解和氧化反应合成了中间体3,5,6-三甲基吡嗪-2-甲醛（4）; 4与取代N-4-哌啶酮发生缩合反应合成了9个新型的川芎嗪衍生物，其结构经¹H NMR, ¹³C NMR和MS（ESI）表征。     

川芎嗪衍生物的设计、合成及抗血小板凝集活性研究

分别以川芎嗪(TMP)和邻苯二胺为起始原料,经KMn O4氧化、酯缩合、环化、还原等步骤合成了7个新型的川芎嗪衍生物,其结构经1H NMR、13C NMR及HRMS确证。并采用Born比浊法初步测试了化合物的体外抗血小板凝集活性。结果表明,化合物3和7对二磷酸腺苷(ADP)诱导的血小板凝集抑制率IC50分别为0.23mmol/L和0.27mmol/L,优于母体化合物川芎嗪(0.42mmol/L)。     

利用Mitsunobu反应合成川芎嗪衍生物

以川芎嗪为起始原料,利用Mitsunobu反应合成了三个3,5,6.三甲基吡嗪.2-基-甲氧基苯甲醛衍生物,收率87%～92%.其结构经1H NMR,13C NMR和ESI-MS表征.     

吡嗪类化合物的合成及其抗血小板凝集活性测试

为提高川芎嗪的抗血小板凝集活性,分别以不同的二胺、2,3-丁二酮和硫辛酸为起始原料,采用溴代、水解、环化、氧化、氢化、取代等反应,通过四条路线合成了7个川芎嗪衍生物,其结构经1H NMR、13C NMR及ESI-MS确证。采用Born比浊法初步测试了化合物的体外抗血小板凝集活性,结果显示,化合物1(IC50=0. 26mmol/L)、2(IC50=0. 27mmol/L)和7(IC50=0. 21mmol/L)对由二磷酸腺苷(ADP)诱导的血小板凝集具有一定的抑制活性,优于先导化合物川芎嗪(IC50=0. 49mmol/L)。因此,在不改变川芎嗪药效团的前提下对其进行不同程度的环化,能明显提高川芎嗪的抗血小板凝集活性,此研究为后期化合物的结构修饰提供了一定的参考价值。     

生物高分子液晶的新家族——甲壳素及其衍生物

讨论了生物高分子甲壳素及其衍生物形成液晶态的基本结构条件。简要介绍了为制备液晶性甲壳素衍生物所必须的一些主要的化学修饰途径。综述了十几年来甲壳素衍生物（主要是壳聚糖及其衍生物）液晶性的研究进展。介绍了甲壳素及其衍生物的液晶纺丝及其应用前景。指出甲壳素衍生物已成为纤维素之外生物高分子液晶的一个新的大家族。     

二茂铁及其衍生物的合成与应用研究进展

近年来二茂铁及其衍生物的合成与应用研究是金属有机化学研究的热点.本文不仅对二茂铁及其衍生物的性质、合成及其应用研究现状作了归纳和评述,而且简要概括了二茂铁及其衍生物的未来研究方向.     

吡唑啉酮衍生物及其金属配合物抗肿瘤研究进展

综述了吡唑啉酮衍生物及其金属配合物抗肿瘤生物活性国内外研究进展,主要包括吡唑啉酮衍生物及其金属配合物抗肿瘤生物活性,及其活性作用机制。展望了吡唑啉酮衍生物及其金属配合物抗肿瘤活性研究的发展方向。     

Synthesis of Novel Ligustrazine Derivatives as Potential Platelet Aggregation Inhibitors

Ligustrazine (lig; tetramethylpyrazine, TMP; Figure 1) is one of major efficient components from Chinese traditional medicine herb Ligusticum Chuanxiong Hort, which is currently widely used in China for the treatment of coronary atherosclerotic cardiovasc…     

Synthesis and NHE1 inhibitory activity of ligustrazine derivatives

A series of novel derivatives of ligustrazine linked with substituted benzoyl guanidine were synthesized. These compounds have not been reported in literature, and their chemical structures were confirmed by IR, 1H NMR and MS. The results of NHE1 inhibitory activity test showed that compounds I2, I3, I4, I6, and I7 possess more potent NHE1 inhibitory activity than cariporide.     

Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents

To discover new anti-cancer agents with multi-effect and low toxicity, a series of ligustrazine derivatives were synthesized using several effective anti-tumor ingredients of Shiquandabu Wan as starting materials. Our idea was enlightened by the "combination principle" in drug discovery. The ligustrazine derivatives' anti-tumor activities were evaluated on the HCT-8, Bel-7402, BGC-823, A-549 and A2780 human cancer cell lines. In addition the angiogenesis activities were valued by the chick chorioallantoic membrane (CAM) assay. 1,7-bis(4-(3,5,6-Trimethylpyrazin-2-yl)-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (4) and 3 α,12 α-dihydroxy-5β-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (5) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD?? value of the compound 5 exceeded 3.0 g/kg by oral administration in mice.     

Preparation of molecularly imprinted adsorptive resin for trapping of ligustrazine from the traditional Chinese herb Ligusticum chuanxiong Hort

A highly selective molecularly imprinted adsorptive resin for ligustrazine was prepared by melamine-urea-formaldehyde (MUF) gel. In the experiments, two pieces of MUF gel were synthesized firstly; one was added ligustrazine hydrochloride as the template molecule in it to prepare the imprinted adsorptive resin, and the other was not. Scanning electron microscopy (SEM) revealed that both resins were the porous with a network structure whether or not it was added template molecule. The imprinted adsorptive resin had an absorbability of 85.22% measured by a 200 mg L⁻¹ solution of ligustrazine hydrochloride at room temperature. The resin of MUF without template, on the other hand, displayed an adsorption capacity of almost zero. It illuminated the imprinted adsorptive resin formed ligustrazine recognition sites when the template molecule had been eluted. In the present paper, ligustrazine was effectively separated and enriched from herbs by using a solid-phase adsorptive column filled with the imprinted adsorptive resin. Its eluate, obtained from three kinds of solvents, was analyzed by GC-MS, and the results indicated that the imprinted adsorptive resin showed a high selectivity for ligustrazine. This is believed to be beneficial for extracting natural and highly purified ligustrazine.     

Analysis of Chuanxiong Rhizoma substrate on production of ligustrazine in endophytic Bacillus subtilis by ultra high performance liquid chromatography with quadrupole time‐of‐flight mass spectrometry

Ligustrazine was the active ingredient of the traditional Chinese medicine Chuanxiong Rhizoma. However, the content of ligustrazine is very low. We proposed a hypothesis that ligustrazine was produced by the mutual effects between endophytic Bacillus subtilis and the Ligusticum chuanxiong Hort. This study aimed to explore whether the endophytic B. subtilis LB5 could make use of Chuanxiong Rhizoma fermentation matrix to produce ligustrazine and clarify the mechanisms of action preliminarily. Ultra high performance liquid chromatography with quadrupole time‐of‐flight mass spectrometry analysis showed the content of ligustrazine in Chuanxiong Rhizoma was below the detection limit (0.1 ng/mL), while B. subtilis LB5 produced ligustrazine at the yield of 1.0268 mg/mL in the Chuanxiong Rhizoma‐ammonium sulfate fermentation medium. In the fermented matrix, the reducing sugar had a significant reduction from 12.034 to 2.424 mg/mL, and rough protein content increased from 2.239 to 4.361 mg/mL. Acetoin, the biosynthetic precursor of ligustrazine, was generated in the Chuanxiong Rhizoma‐Ammonium sulfate (151.2 mg/mL) fermentation medium. This result showed that the endophytic bacteria B. subtilis LB5 metabolized Chuanxiong Rhizoma via secreted protein to consume the sugar in Chuanxiong Rhizoma to produce a considerable amount of ligustrazine. Collectively, our preliminary research suggested that ligustrazine was the interaction product of endophyte, but not the secondary metabolite of Chuanxiong Rhizoma itself.     

哌啶并[2,3-b]哌嗪类衍生物的设计、合成及其抗血小板聚集活性研究

以2,3-二氨基吡啶和2,3-丁二酮为起始原料,经环化、催化氢化和亲核取代反应合成了10个新型哌啶并[2,3-b]哌嗪类衍生物(3a~3j),其结构经¹H NMR、¹³C NMR和HR-MS确证。体外抗血小板聚集活性研究表明,化合物3d、3e、3g、3h和3j具有一定的抗血小板聚集作用,其中化合物3h(IC₅₀=1.24mmol/L)的活性显著优于母体化合物川芎嗪(IC₅₀=3.96mmol/L)和阳性药物阿司匹林(IC₅₀=2.41mmol/L)。     

固相萃取-高效液相色谱法测定人血浆中的川芎嗪

建立了高效液相色谱测定人血浆中川芎嗪浓度的方法。色谱条件:分析柱为Luna C18(150 mm×4.6 mm i.d.,5 μ m),流动相为甲醇-乙腈-醋酸盐缓冲液(pH 5.0)(体积比为50∶8∶42),流速1.0 mL/min,柱温40 ℃,检测波长280 nm。 血浆样品预处理采用C8固相小柱萃取法。方法的线性范围为25～5000 μg/L,线性相关系数为0.9999。高、中、低浓度 的川芎嗪在标准血浆样品中的平均提取回收率为96.72％～100.90％,日内和日间相对标准偏差(RSD)小于8.64％,准确度 为99.59%~103.26%,检测限为10 μg/L。该方法的各项效能指标符合生物样品的分析要求,可用于川芎嗪制剂的人体药 代动力学研究。     

Determination of Gastrodin and Ligustrazine Hydrochloride in Plasma and Brain Dialysate by LC–Tandem MS

A gradient liquid chromatography-tandem mass spectrometry method has been developed and validated for the determination of gastrodin and ligustrazine hydrochloride in rat plasma and brain dialysates. Zolpidem was used as internal standard. For plasma samples, solid-phase extraction was used and the brain dialysates were collected from freely moving rats using brain microdialysis. Both were followed by HPLC separation and positive electrospray ionization tandem mass spectrometry detection (ESI–MS–MS). Chromatographic separation was achieved on a Symmetry RP-18 column using gradient elution with methanol and water containing 0.5% formic acid and 2 mM ammonium formate. Selected reaction monitoring (SRM) mode was used for quantitation. Good linearities were obtained in the range of 0.05–100 and 0.01–50 μg mL^?1 for gastrodin and ligustrazine hydrochloride in rat plasma, and 0.05–1,000 ng mL^?1 for both in dialysate. The lower limit of quantitation was 0.01 ng mL^?1 for gastrodin and 0.05 ng mL^?1 for ligustrazine. The method is precise and reliable and can be applied to pharmacokinetic studies.