青蒿素及其一类物结构和合成的研究——ⅩⅩⅣ.青蒿素转化为天然的△~(11(13))-脱氢青蒿素(英文)

本文首次报道从青蒿素(2)转变为△~(11(13))-脱氢青蒿素(1)的结果。青蒿素(2)在 LDA 存在下,与溴苯硒反应,得到11-苯硒基青蒿素(3)(27％)、11-溴代青蒿素(4)(15％),△~(11(13))-脱氢青蒿素(1)和△~(7(11)-脱氢青蒿素(5)(46％)。用二苯二硒的硒化反应只回收原料青蒿素。3用30％H_2O_2氧化,生成天然的1,产率95％。根据CD 光谱,推定3中的苯硒基和4中的溴原子均处于α-构型。     

青蒿素及其类似物的合成研究-由青蒿素降解产物重组青蒿素

青蒿素1是中药青蒿(Artemisia annua L.)中的抗疟有效成份,它具有与其他抗疟药完全不同的独特结构,近年来,李英等已报道了从青蒿素合成得一系列疗效更高的衍生物,而Schmid等和许杏祥等曾分别独立完成了青蒿素的合成。由于合成其它青蒿素衍生物的需要,我们计划发展较为实用的方法。鉴于目前易于获得天然的青蒿素,因此我们在研究全合成的同时,也探索利用由青蒿素获得接力中间体重组青蒿素和合成青蒿素衍生物。通过酸性降解研究,我们从青蒿素经两步可制得双酮酯化合物3,产率较高。该化合物保持青蒿素中原有的构型,因此是一个理想的接力中间体,本文报道由此化合物重组青蒿素的工作。     

青蒿素类化合物的发现过程与研究现状

2015年,屠呦呦因创制新型抗疟药——青蒿素成为我国本土培养的第一位获得诺贝尔自然科学奖的科学家。本文回顾了青蒿素作为高效抗疟药的发展历程,并对青蒿素类化合物的发现过程和研究状况进行了简要概述。     

青蒿素的发现及其获奖启示

青蒿素的发现被国际社会认为是中国继麻黄素之后的第二大医学贡献,屠呦呦研究员由于在青蒿素的发现中作出重大贡献而获得2011年度美国拉斯克临床医学研究奖。通过对青蒿素的发现过程和化学结构确定的简单介绍谈几点教学思考。     

青蒿素与转铁蛋白相互作用的光谱分析

应用分子荧光光谱与紫外-可见吸收光谱法研究了青蒿素与转铁蛋白分子间的相互作用,发现青蒿素对转铁蛋白有荧光猝灭作用,并对其作用机理做了探讨。依据F ster非辐射能量转移理论,测定了在30℃时,转铁蛋白-青蒿素间的结合常数(K=1.74×105L/mol)和结合位点数(n=0.696),结合距离(r=1.94nm);并采用同步荧光技术考察了青蒿素对转铁蛋白构象的影响。     

青蒿素生物合成的研究III: 青蒿素和青蒿素B生物合成中的关键性中间体-青蒿素

以[15-^3H]青蒿酸为前体用青蒿匀聚浆体进行青蒿素和青蒿素B的生物合成.实验结果表明, 在青蒿植物由MVA生物合成青蒿素和青蒿素B的途径中, 青蒿酸是关键性中间体.     

药物青蒿素与溶菌酶相互作用研究

应用荧光光谱、紫外-可见光谱法研究了青蒿素与溶菌酶的相互作用,发现青蒿素对溶菌酶荧光有猝灭作用。以Lineweaver-Burk双倒数方程和能量传递原理分别计算了二者反应的结合常数(K25℃=646.4L/mol,K35℃=518.8L/mol)和作用距离(r=3.08nm)。实验表明,随着温度升高,溶菌酶与青蒿素的猝灭曲线斜率降低,证明了二者的相互结合作用为单一的静态猝灭过程,其作用机制属能量转移机制。通过测定热力学参数,判断了青蒿素和溶菌酶之间的作用力类型,青蒿素与溶菌酶以疏水作用力相结合,导致溶菌酶内源荧光的静态猝灭。通过青蒿素与溶菌酶的结合反应,探讨了药物青蒿素在生物体内与蛋白酶的相互作用机理。     

以青蒿素为背景培养化学学科核心素养的教学设计——科学家怎样研究有机物

基于“青蒿素”的发现历程,开展 “科学家怎样研究有机物”(第1课时)的教学设计,向学生还原科学家在不同阶段研究青蒿素时的场景,为培养学生化学学科核心素养提供新的思路。     

大孔吸附树脂提取青蒿素的研究

探讨了大孔吸附树脂提取青蒿素的方法。以青蒿素的吸附量,青蒿素含量,青蒿素收率和提取率为考察指标,确定大孔吸附树脂提取青蒿素的工艺条件。研究结果表明,ADS-17树脂对青蒿素的吸附量大,解吸容易,可用于提取黄花蒿中青蒿素的工业化生产,其工艺条件为:青蒿素最大吸附量为112.30mg/g,吸附流速为2BV/h,洗脱剂为90%乙醇,解吸流速为2BV/h,青蒿素含量大于99%,收率高达0.3%,提取率高达75%以上。     

青蒿素及其衍生物抗疟活性的密度泛函理论研究

为了深入研究青蒿素及其衍生物的抗疟活性和分子结构之间的关系,运用密度泛函理论B3LYP方法,以6-31G*为基组对青蒿素及其衍生物二氢青蒿素、蒿甲醚和青蒿琥酯进行了优化计算.从分子的几何构型、NBO电荷及前线轨道能等方面分析了青蒿素及其衍生物的抗疟活性与结构之间的关系.青蒿素及其衍生物结构中的过氧桥键是其抗疟作用的活性位,O17和O_20带负电荷越多、ΔE_(LUMO-HOMO)越低、E_(HOMO)能级越高,分子的抗疟活性越强.结果表明,4种化合物的抗疟活性顺序为:青蒿素二氢青蒿素蒿甲醚青蒿琥酯,与临床实验结果相吻合.     

A Continuous‐Flow Process for the Synthesis of Artemisinin

Isolation of the most effective antimalarial drug, artemisinin, from the plant sweet wormwood, does not yield sufficient quantities to provide the more than 300 million treatments needed each year. The high prices for the drug are a consequence of the unreliable and often insufficient supply of artemisinin. Large quantities of ineffective fake drugs find a market in Africa. Semisynthesis of artemisinin from inactive biological precursors, either dihydroartemisinic acid (DHAA) or artemisinic acid, offers a potentially attractive route to increase artemisinin production. Conversion of the plant waste product, DHAA, into artemisinin requires use of photochemically generated singlet oxygen at large scale. We met this challenge by developing a one‐pot photochemical continuous‐flow process for the semisynthesis of artemisinin from DHAA that yields 65 % product. Careful optimization resulted in a process characterized by short residence times. A method to extract DHAA from the mother liquor accumulated during commercial artemisinin extractions, a material that is currently discarded as waste, is also reported. The synthetic continuous‐flow process described here is an effective means to supplement the limited availability of artemisinin and ensure increased supplies of the drug for those in need.     

Quantitative determination of artemisinin in rat hemolyzed plasma by an HPLC–HRMS method

Iron present in hemolyzed plasma could cause the degradation of artemisinin by reductively cleaving the peroxide bridge of artemisinin during sample preparation, which is a significant technical challenge for artemisinin determination. In this paper, this issue was resolved by using sodium nitrite as methemoglobin-forming agent to oxidize hemoglobin to methemoglobin in the presence of acetic acid and prevent the degradation of artemisinin in hemolyzed plasma during the sample preparation procedure. Then, a high-performance liquid chromatography tandem high-resolution mass spectrometry method was developed and validated for the determination of artemisinin in normal and hemolyzed plasma. The linear range was validated over the concentration range of 5–500 ng ml⁻¹. The matrix effect and stability were also evaluated. This robust and sensitive assay was successfully applied to a pharmacokinetic study in rats after an oral administration of Artemisia annua L. extract.     

青蒿素及其衍生物电化学性质的研究Ⅱ: 青蒿素在 氯化血红素存在下的还原

用电化学方法研究了青蒿素与氯化血红素之间的相互作用。青蒿素在玻璃碳电极上于-1.08V处发生一个2电子转移的不可逆还原。但是,即使在低至4.0×10^-^8mol/L氯化血红素存在下,青蒿素仍可被催化还原,阴极过电位降低了600mV。配合物EDTA-Fe(Ⅲ)具有类似氯化血红素的催化性质,它降低了QHS阴极过电位590mV。在这个体系中,青蒿素在碳电极上的还原是一个借助于氯化血红素催化的还原过程,氯化血红素的存在降低了青蒿素还原活化能,促进了青蒿素的分解。文中讨论了该反应的还原机理。     

Molecular Basis of Artemisinin Derivatives Inhibition of Myeloid Differentiation Protein 2 by Combined in Silico and Experimental Study

Artemisinin (also known as Qinghaosu), an active component of the Qinghao extract, is widely used as antimalarial drug. Previous studies reveal that artemisinin and its derivatives also have effective anti-inflammatory and immunomodulatory properties, but the direct molecular target remains unknown. Recently, several reports mentioned that myeloid differentiation factor 2 (MD-2, also known as lymphocyte antigen 96) may be the endogenous target of artemisinin in the inhibition of lipopolysaccharide signaling. However, the exact interaction between artemisinin and MD-2 is still not fully understood. Here, experimental and computational methods were employed to elucidate the relationship between the artemisinin and its inhibition mechanism. Experimental results showed that artemether exhibit higher anti-inflammatory activity performance than artemisinin and artesunate. Molecular docking results showed that artemisinin, artesunate, and artemether had similar binding poses, and all complexes remained stable throughout the whole molecular dynamics simulations, whereas the binding of artemisinin and its derivatives to MD-2 decreased the TLR4(Toll-Like Receptor 4)/MD-2 stability. Moreover, artemether exhibited lower binding energy as compared to artemisinin and artesunate, which is in good agreement with the experimental results. Leu61, Leu78, and Ile117 are indeed key residues that contribute to the binding free energy. Binding free energy analysis further confirmed that hydrophobic interactions were critical to maintain the binding mode of artemisinin and its derivatives with MD-2.     

Simultaneous isolation of artemisinin and its precursors from Artemisia annua L. by preparative RP-HPLC

It is still a major challenge to simultaneously isolate artemisinin and its precursors, especially dihydroartemisinic acid and artemisinic acid, from herbal Artemisia annua. A rapid, economical and automatical chromatographic separation process to isolate and purify artemisinin, dihydroartemisinic acid and artemisinic acid at the same time on a preparative scale was developed. The procedure included solvent extraction of ground Artemisia annua leaves by refluxing and purification of crude extract by preparative reverse-phase high-performance liquid chromatography (RP-HPLC). Fractions containing artemisinin and its precursors were collected and identified by gas chromatography and mass spectrometry. High purity of artemisinin, dihydroartemisinic acid and artemisinic acid was obtained by preparative HPLC with a C(18) column and 60% acetonitrile in water as the mobile phase. The techniques described here are useful tools for the preparative-scale isolation of artemisinin and its precursors in a fast, cost-effective and environmental friendly manner.     

不同电极上血红素对青蒿素的电催化还原

 在含20%乙醇的Britton-Robinson缓冲液介质(pH=7.2)中,采用循环伏安法在玻碳电极和银电极上比较了血红素对青蒿素还原的催化作用. 由于血红素和青蒿素加合物的形成及血红素中Fe2+的催化作用,青蒿素在玻碳电极和银电极上的还原过电位分别降低了0.32和0.09 V,还原活化能分别降低了62.1和17.6 kJ/mol. 还比较了血红素和配合物EDTA-Fe3+对青蒿素的催化还原效果,结果表明,EDTA-Fe2+的催化作用远低于血红素. 进一步证实了血红素在青蒿素的药理研究中起着关键作用.     

青蒿素的生物素标记衍生物的合成

青蒿素1及其衍生物具有特征的过氧桥结构, 并呈现优秀的抗疟生物活性. 为了研究详细的作用机制和确定生物学作用靶标, 本研究从易得的青蒿素衍生物出发, 通过酰胺键相连, 合成了生物素标记的青蒿素衍生物.     

Synthesis of N~(11)-anchoring biotinylated artemisinin derivatives and their preliminary biological assessment

Unique endoperoxide moiety of artemisinin and its derivatives has been considered the functionality exhibiting highly potent antimalarial and anticancer activities.To investigate the mechanisms of their biological actions,development of suitable molecular probes including biotinylated derivatives is of extreme significance.The synthesis and preliminary biological assessment of four new biotinylated artemisinin derivatives have been reported in this work.     

Intramolecular chain reaction of artemisinin oxidation

The intramolecular chain oxidation of artemisinin was analyzed using the parabolic model. The competition of the mono- and bimolecular peroxy radicals formed from artemisinin was considered. Artemisinin is predominantly oxidized via the intramolecular chain mechanism to form polyatomic hydroperoxides. This results in the situation when, under aerobic conditions, artemisinin is transformed from the monofunctional into polyfunctional initiator with several hydroperoxide groups. The enthalpy was calculated, and the activation energies and rate constants of the intramolecular reactions of the artemisinin peroxy radicals, as well as those of their bimolecular reactions with C-H, S-H, and O-H bonds of biological substrates and their analogs, were calculated in the framework of the parabolic model. A new kinetic scheme for artemisinin oxidation was proposed. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 267–275, February, 2008.