雷公藤甲素及其衍生物的合成研究进展

综述了雷公藤甲素及其衍生物的化学合成与结构修饰研究进展.参考文献40篇.     

反相高效液相色谱法测定雷公藤提取物中雷公藤甲素含量

应用反相高效液相色谱法检测了雷公藤提取物中雷公藤甲素的含量。样品经洗脱提取后,以Ｃ１８化学键合硅胶为固定相,乙腈－水（４０∶６０,Ｖ／Ｖ）为流动相,用２１０ｎｍ波长定量检测。测定结果表明,雷公藤甲素浓度在０．２５～４．００ｍｇ／Ｌ范围内线性良好,最低进样检测浓度为０．１ｍｇ／Ｌ。批内（ｎ＝５）及批间（ｎ＝５）测定相对标准偏差分别为１．９％～６．５％和２．７％～７．８％,回收率为８９．８％～９２．０％。     

冬凌草甲素葡萄糖苷的合成

为研究冬凌草甲素的构效关系,合成生物活性更高的化合物,以冬凌草甲素为先导化合物,通过对其进行选择性保护,再进行糖苷化,最后脱保护,经五步反应,以23.0%的总收率,合成了冬凌草甲素-6-O-β-D-葡萄糖苷,并得到一系列冬凌草甲素衍生物,它们的结构经IR,1H NMR,MS和元素分析确证.     

气相色谱-电子捕获法测定血浆中的雷公藤甲素

 血浆样品经碱化后用乙醚 氯仿 (体积比为 3∶1)混合液提取 ,浓缩的提取物与三氟醋酐进行衍生化反应 ,用气相色谱法分离、63Ni电子捕获检测器测定雷公藤甲素的含量。色谱柱为SE 5 430m× 0 2 5mmi d 交联石英毛细管柱。雷公藤甲素的质量浓度在 1 0 μg/L～ 5 0 0 μg/L范围内与峰面积线性关系良好 (r =0 9990 ) ,在血浆中的平均回收率为 96 3% ,最小检测限为 0 5 μg/L。方法重现性好 ,准确、灵敏 ,无杂质干扰 ,数据准确可靠 ,可用于临床生物样品中雷公藤甲素含量的测定。     

高效液相色谱梯度法测定雷公藤制剂中雷公藤甲素的含量

采用高效液相色谱梯度法分离测定雷公藤制剂中雷公藤甲素的含量,用国产YWG色谱柱分离,二极管阵列检测器检测,所得三维光谱与空白光谱进行差减,取波长218nm处色谱图积分,定量。与等度法比较,梯度法具有更高的分离度、灵敏度,测定雷公藤口服液中雷公藤甲素的质量浓度为202．0μg／L,每片雷公藤片剂含甲素11．74μg,结果显著低于等度法和标示量（P<0．05）。     

微乳液毛细管电动色谱法测定大鼠滑膜细胞中雷公藤甲素的含量

建立微乳液毛细管电动色谱法快速测定大鼠滑膜细胞内外液中雷公藤甲素含量的方法.在雷公藤甲素不同给药时间孵育条件下,将滑膜细胞分为空白对照组和给药组,测定滑膜细胞内外液中雷公藤甲素含量,并比较了细胞外液中雷公藤甲素在不同给药时间的含量变化.毛细管电泳运行缓冲液组成:1％(w/V)SDS,3％(V/V)正丁醇,1％(V/V)乙酸乙酯,96％(V/V)5 mmol/L硼砂-10 mmol/L磷酸盐溶液,pH 9.0;运行电压:25 kV;压力进样:0.5 psi×6 s;电泳操作温度:25℃;检测波长:214 nm.结果表明,细胞内外液中的雷公藤甲素所呈现的线性关系良好,相关系数分别为0.9995和0.9991.当给药24h时,细胞内外液中的雷公藤甲素浓度分别为0.736和20.745 μg/mL.本方法简单准确、灵敏度高、精密度好,可用于滑膜细胞内外液中雷公藤甲素浓度的动态变化规律研究,为进一步研究中药有效成分对滑膜细胞功能和活性的影响提供方法学基础.     

反相高效液相色谱测定雷公藤浸膏中甲素的含量

报道了液固萃取-反相高效液相色谱法测定雷公藤浸膏(乙酸乙酯提取物)中甲素含量的方法。用LichrospherC18色谱柱，以甲醇：水-60：40(V／V)溶液为流动相，检测波长218nm。方法回收率为99．4％，变异系数为0．53％，方法快速，重现性及准确度能满足雷公藤浸膏中甲素含量测定的要求。     

RP-HPLC测定雷公藤甲素聚乳酸纳米粒的包封率及载药量

本文研究了反相高效液相色谱和超速冷冻离心测定雷公藤甲素聚乳酸纳米粒包封率和载药量的方法。实验结果表明,在优化色谱条件下雷公藤甲素与辅料及溶剂峰分离良好,雷公藤甲素在1.84～46μg·mL-1范围内本法有良好的线性关系(r=1.0,n=6),方法日内及日间精密度分别为0.09%～1.01%及0.5%～2.12%,在空白聚乳酸纳米粒中雷公藤甲素的加样回收率为98.85%～100.48%,聚乳酸包裹的雷公藤甲素纳米粒的包封率分别为74.27%、60.37%、46.6%,其相对应的载药量分别为1.36%、1.95%、2.57%。此方法准确可靠、简单、重现性好。     

快速溶剂萃取-凝胶渗透色谱净化-液相色谱-质谱法测定动物肝组织中雷公藤甲素和雷公藤酯甲

提出了动物肝组织中雷公藤甲素与雷公藤酯甲的液相色谱-质谱法分析方法。用快速溶剂萃取仪用乙腈将动物肝组织中雷公藤甲素与雷公藤酯甲萃取到有机相,提取液经凝胶渗透色谱净化除去基质的干扰,所得洗脱液40℃氮吹挥干后用甲醇定容至0.5mL,用液相色谱-质谱法测定。雷公藤甲素与雷公藤酯甲的质量浓度均在5～1 000μg.L-1范围内呈线性,检出限(3S/N)均为1.0μg.L-1。在动物肝组织中用标准加入法做回收及精密度试验,结果为:雷公藤甲素和雷公藤酯甲的回收率分别在69.3%～77.8%,73.1%～77.2%之间;雷公藤甲素和雷公藤酯甲测定值的相对标准偏差(n=5)分别在3.2%～3.3%,2.3%～3.0%之间。     

雷公藤甲素对大鼠尿样代谢物影响的核磁共振波谱研究

本文采用基于核磁共振的代谢组学方法研究了雷公藤甲素急性中毒大鼠尿样的代谢特征。结果表明给药后代表肝毒性生化指纹的creatine 和taurine相对含量升高,代表能量代谢的citrate, succinate, α-oxoglutarate相对含量下降,反应肠道菌群代谢状况的trimethylamine N-oxide,和hippurate等也异常,并且这些变化在的药物作用后16小时达到最大,56小时后大部分代谢物的浓度恢复正常。另外,在0~16小时实验组样品里观察到了被认为是一种新的急性肝中毒的生化标记物2’-deoxycytidine。以上NMR实验结果表明雷公藤甲素可能影响大鼠的肠道菌群和能量代谢,引发急性肝损伤和轻度肾衰竭。对注射组大鼠血浆的生化分析和肝组织的病理学切片也证明了实验大鼠肝功能的异常现象。以上结果说明NMR实验信息有助于进一步从分子水平上阐明雷公藤甲素的毒理学和药理学机制。     

Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters

A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5'-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 - 2.3 mM in Caco-2 and 2.0 - 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 - 5.31 x 10(-6 )cm/sec) and floxuridine (0.48 x 10(-6 )cm/sec) were much higher than that of 5-FU (0.038 x 10(-6) cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.     

Synthesis of nucleoside boranophosphoramidate prodrugs conjugated with amino acids

[structure: see text] Nucleoside boranophosphates and nucleoside amino acid phosphoramidates have been shown to be potent antiviral and anticancer agents with the potential to act as nucleoside prodrugs. A combination of these two types of compounds results in a boranophosphoramidate linkage between the nucleoside and amino acid. This new class of potential prodrugs is expected to possess advantages conferred by both types of parent compounds. Two approaches, specifically the H-phosphonate and oxathiaphospholane approaches, are described here to synthesize nucleoside boranophosphoramidate prodrugs conjugated with amino acids. The H-phosphonate approach involves a key intermediate, silylated nucleoside amino acid phosphoramidite 6, prepared from a series of reactions starting from nucleoside H-phosphonate in the presence of condensing reagent DPCP. Due to the lengthy procedure and the difficulties in removing DPCP from the final products, we switched to the oxathiaphospholane approach in which the DBU-assisted oxathiaphospholane ring-opening process constituted a key step for the generation of nucleoside amino acid boranophosphoramidates 24. We demonstrate that this key step did not cause any measurable C-racemization of boranophosphorylated amino acids 22. Diastereomers of compounds 24a-f were separated by RP-HPLC. An "adjacent"-type mechanism is proposed to explain the diastereomer ratio in the final products obtained via the oxathiaphospholane approach. A tentative assignment of configuration for the diastereomers was carried out based on the mechanism, molecular modeling, and (1)H NMR. Conclusively, the oxathiaphospholane methodology proved to be more facile and efficient than H-phosphonate chemistry in the preparation of the nucleoside amino acid boranophosphoramidate analogues that are promising as a new type of antiviral prodrugs.     

Biotransformation of triptolide by Cunninghamella blakesleana

Biotransformation of triptolide 1 by Cunninghamella blakesleana (AS 3.970) was carried out. Seven biotransformation products were obtained and four of them were characterized as new compounds. On the basis of their NMR and mass spectral data, their structures were characterized as 5α-hydroxytriptolide 2, 1β-hydroxytriptolide 3, triptodiolide 4, 16-hydroxytriptolide 5, triptolidenol 6, 19α-hydroxytriptolide 7 and 19β-hydroxytriptolide 8. All the new transformed products (2, 3, 7 and 8) were found to exhibit potent in vitro cytotoxicity against some human tumor cell lines.     

Efficient synthesis of nucleoside aryloxy phosphoramidate prodrugs utilizing benzyloxycarbonyl protection

An efficient method for the synthesis of nucleoside phosphoramidates prodrugs (6a-f) has been developed that employs a simple protection/deprotection sequence of the nucleoside with benzyloxycarbonyl (Cbz). The coupling reaction of Cbz-protected derivatives (5a-f) with phenyl-(ethoxy-l-alaninyl)-phosphorochloridate (7), followed by Cbz group removal by hydrogenolysis provided the phenyl phosphoramidate ProTides (6a-f) in excellent overall yields.     

Synthesis of an anion-binding amino acid

We achieved the synthesis of a derivative of phenylalanine with a diazamacrocycle on its side chain by macrocyclization of a dichloride on l-DOPA. We also report its incorporation into peptide structures by solid phase peptide synthesis which will lead to the development of artificial anion channels.     

Design, synthesis and preliminary biological evaluation of brain targeting L-ascorbic acid prodrugs of ibuprofen

L-Ascorbic acid（AA,vitamin C） exhibits a high concentration in the brain.The transportation of AA in brain is mainly mediated by the glucose transporter 1（GLUT₁） and the Na⁺-dependent vitamin C transporter SVCT₂.While L-ascorbic acid C6-O conjugation has been investigated as a tool to enhance brain drug delivery,C5-O conjugation and C5-O & C6-O conjugation as brain targeting tools have not been reported.In this letter,ibuprofen was linked directly to C5-O,C6-O and C5-O & C6-O positions of L-ascorbic acid with eater bonds,providing prodrug 1,2 and 3,respectively,to improve their targeting abilities in the brain.Prodrug 1,2 and 3 were synthesized in facile ways with good yields.And the preliminary evaluation in vivo illustrated that prodrug 2 had a better targeting ability than prodrug 1. Moreover,prodrug 3,whose C5-O & C6-O positions were both modified,had good targeting ability for brain which will provide an important evidence for our further study on C5-0- & C6-0- di-derivatives of L-ascorbic acid.     

Effect of CYP3A4 on liver injury induced by triptolide

Triptolide (TP), one of the main bioactive diterpenes of the herbal medicine Tripterygium wilfordii Hook F, is used for the treatment of autoimmune diseases in the clinic and is accompanied by severe hepatotoxicity. CYP3A4 has been reported to be responsible for TP metabolism, but the mechanism remains unclear. The present study applied a UPLC–QTOF–MS-based metabolomics analysis to characterize the effect of CYP3A4 on TP-induced hepatotoxicity. The metabolites carnitines, lysophosphatidylcholines (LPCs) and a serious of amino acids were found to be closely related to liver damage indexes in TP-treated female mice. Metabolomics analysis further revealed that the CYP3A4 inducer dexamethasone improved the level of LPCs and amino acids, and defended against oxidative stress. On the contrary, pretreatment with the CYP3A4 inhibitor ketoconazole increased liver damage with most metabolites being markedly altered, especially carnitines. Among these metabolites, except for LPC18:2, LPC20:1 and arginine, dexamethasone and ketoconazole both affected oxidative stress induced by TP. The current study provides new mechanistic insights into the metabolic alterations, leading to understanding of the role of CYP3A4 in hepatotoxicity induced by TP.     

TFAA-H3PO4 mediated rapid and single-step synthesis of mutual prodrugs of paracetamol and NSAIDs

Abstract

A clean and operationally simple method has been developed for the preparation of mutual prodrug using paracetamol and various nonsteroidal anti-inflammatory drugs. The methodology involves use of TFAA/H₃PO₄ in acetonitrile and a variety of mutual prodrugs has been prepared in good yields by using this single-step C–O bond forming reaction.

     

Studies on the reductively triggered release of heterocyclic and steroid drugs from 5-nitrothien-2-ylmethyl prodrugs

Hypoxia (inadequate concentrations of dioxygen in tissues) is present in several disease states, including cancer and rheumatoid arthritis. Prodrug systems, which after bioreduction, selectively release active drugs in these tissues may be important in therapy. The 5-nitrothien-2-ylmethyl ester of aspirin was synthesised by treatment of 5-nitrothiophene-2-methanol with 2-acetoxybenzoyl chloride, whereas that of prednisolone hemisuccinate was prepared by reaction of prednisolone with 5-nitrothien-2-ylmethyl pentafluorophenyl butanedioate. In chemical model systems, both of these ester-linked potential prodrugs suffered hydrolysis, rather than reductively triggered release of the corresponding drug. 1-(5-Nitrothien-2-ylmethoxy)isoquinolines released the corresponding isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) rapidly upon reduction of the nitro group with sodium borohydride/palladium, showing that these may be useful as reductively triggered prodrugs. In approaches to N-linked potential prodrugs, isoquinolin-1-one and nifedipine (a 1,4-dihydropyridine Ca²⁺ channel antagonist) were alkylated at nitrogen by 2-chloromethylthiophene but the corresponding 5-nitrothien-2-ylmethyl derivatives were synthetically inaccessible.