青蒿素类药物抗肿瘤作用的研究

研究表明，青蒿素类抗疟药具有较强的抗肿瘤作用，并且不易产生耐药性和具有靶向杀伤作用，有希望将其开发成为新型的化疗药物和辅助化疗药物用于治疗肿瘤。     

青蒿素及其衍生物的抗肿瘤作用

青蒿素是我国科研人员最早从植物青蒿中提出的半萜内酯化合物，具有很强的抗疟活性，是WHO批准治疗脑型疟疾和恶性疟疾的主要药物之一。近年来，研究发现青蒿素及其衍生物还具有其他方面的功效，如抗肿瘤、抗炎和抗血吸虫病作用明显，引起了广泛关注。     

双氢青蒿素的抗肿瘤作用

青蒿Artemisia annuaL.是中国特有的植物,生长茂盛,分布较广,易于采集,其药用已超过2000年历史。青蒿素(Artemisinin)是从青蒿叶中提取的有效抗疟成分,是我国首先发现的新构型的抗疟药,其分子结构中含有内过氧化基团,带有可交替的O-C-O-C区段,可被打开进行青蒿素衍生物的化学合成。双氢青蒿素(Dihydroartemisinin,DHA)是青蒿素的一个重要衍生物,根据各种文献报道,它的抗疟疗效比较强,是青蒿素类药物在体内的主要活性代谢产物,可能此类药物都是通过其在体内起抗疟作用[1]。DHA分子式为:C15H24O5,化学结构式详见图1。DHA分子量为284,…     

青蒿素及其衍生物的抗肿瘤作用

青蒿素及其衍生物是一类高效、低毒的抗疟药物 ,尤其对耐氯喹或对多种药物耐药的脑型疟和恶性疟有效。因此在临床上得到广泛的应用。随着研究的深入 ,人们发现青蒿素类化合物还具有其它很多重要的药理活性 ,如抗血吸虫、免疫调节、抗心律失常、抗肿瘤等。尤其是其抗肿瘤作用 ,越来越引起研究者们的重视。很多实验研究表明 ,青蒿素类化合物对多种肿瘤细胞的生长具有显著的抑制作用 ,而且对正常组织细胞的毒性很低 ,这为研究开发经济、有效的抗癌药物提供了新的线索。本文就近年来有关青蒿素类药物抗肿瘤的研究进展作一综述。1　青蒿素及其衍…     

青蒿素类化合物抗肿瘤作用机制研究进展

青蒿素及其衍生物不仅具有抗疟活性,还展现出了广泛的抗肿瘤活性。这类化合物通过多种途径实现抗肿瘤作用,包括诱导活性氧生成、阻滞肿瘤细胞增殖周期、引发肿瘤细胞凋亡、抑制肿瘤血管生成、抑制肿瘤细胞的侵袭和转移、克服肿瘤耐药性以及调节肿瘤免疫。本文对青蒿素类衍生物的抗肿瘤作用机制方面的最新研究进展进行了综述。     

抗肿瘤青蒿素衍生物的研究

目的:为抗肿瘤青蒿素衍生物的深入研究和开发提供参考.方法:查阅文献,对抗肿瘤青蒿素衍生物的研究新进展进行归纳总结.结果:高活性的抗肿瘤青蒿素衍生物多为C-10位取代物;青蒿素二聚体及三聚体的抗肿瘤活性可能优于单体衍生物.结论:青蒿素衍生物有望在不久的将来应用于肿瘤治疗.     

青蒿素抗心律失常作用的研究

青蒿素抗心律失常作用的研究王慧珍杨宝峰罗大力张晋廖淑杰１（哈尔滨医科大学药理教研室，哈尔滨１５００８６）中国图书分类号Ｒ９７２．２；Ｒ９７８．６１青蒿素（ａｒｔｅｍｉｓｉｎｉｎ）是一低毒、有效的抗疟药〔１〕，在应用其治疗疟疾的同时，发现该药能使窦性心...     

青蒿素抗肿瘤作用的初步研究

目的 研究菊科植物黄花蒿的单体青蒿素(Artimisinine, ART)的抗肿瘤作用.方法 采用动物移植性肿瘤实验方法.结果 50 mg·kg-1 ART对小鼠移植性肉瘤S180的抑瘤率为37.88%;100 mg·kg-1 ART对小鼠移植性肝癌Heps实体瘤的抑瘤率为35.23%;ART对艾氏腹水癌EAC小鼠生命延长率无统计学意义.结论 ART具有良好的抗肿瘤作用.     

青蒿素类衍生物抗肿瘤研究进展

青蒿素类药物是很好的抗疟药物,近年来大量体内、外研究显示青蒿素具有良好的抗肿瘤活性。大多数肿瘤细胞表面有高浓度的转铁蛋白受体,因此与正常细胞相比,细胞内含有更多的亚铁离子,青蒿素与亚铁离子反应生成自由基,可以选择性的杀伤肿瘤细胞。G1期细胞的转铁蛋白受体表达和铁离子摄入都显著增多,青蒿素类药物在此期诱导细胞凋亡,其具体作用靶点和机制还有待进一步研究,青蒿素衍生物还具有抗肿瘤血管生成活性。将青蒿素类药物与转铁蛋白上的糖基共价结合的复合体,可以将铁离子和青蒿素同时摄入肿瘤细胞,增强了青蒿素的高效性和靶向性。     

影响青蒿素类药物战略发展因素分析

疟疾与贫穷、卫生、环境和政治等因素密切相关,全球每年有100多万人因疟疾死亡,已成为制约全球社会、经济发展的三大疾病之一.由于传统的抗疟药氯喹（CQ）及其替代药周效磺胺＋乙胺嘧啶（SP）日趋严重的抗药性,国际社会已确认青蒿素复方治疗（ACT）药物为最有效的治疗疟疾的手段.复方蒿甲醚是我国研发的具有国际知识产权的药物,由蒿甲醚和本芴醇按固定比例组方,它克服了青蒿素衍生物药物服用次数多、复燃率高和易产生抗药性的缺点,经过近10年约5 000例患者（包括约1 000例儿童）的国际多中心临床试验,2年的南非现场用药试验以及采取了保障贫困人群正确用药的依从性包装,终于在2002年被WHO列入基本药物核心目录,并促使全球抗击艾滋病、结核病和疟疾环球基金（GFATM）同意更改援助计划、增加采购该类药品的资金,成为替代抗药性严重的传统喹啉类药物的最佳药品.     

青蒿素及其衍生物的研究进展

青蒿素类化合物是含过氧桥的化合物,在治疗多药抗药性恶性疟疾方面卓有成效。除此之外,该类化合物还具有抗肿瘤、抗真菌、抗心律失常、抗寄生虫等活性。本文就近年来国内外学者对青蒿素及其衍生物的结构改造及生物活性等方面的研究进行概述。     

青蒿素类药物的药理作用新进展

青蒿素是从植物黄花蒿中提取的抗疟疾的活性成份，目前在临床上广泛用于治疗疟疾。近些年研究发现青蒿素不仅可以抗寄生虫，包括疟原虫、血吸虫，而且具有显著的抗炎、调节免疫和抗肿瘤等多方面的药理作用。本文在介绍青蒿素抗疟疾作用、应用和作用机制的基础上，对近年来青蒿素类药物的其它主要生物学作用研究的现状进行综述。     

Recent advances in artemisinin and its derivatives as antimalarial and antitumor agents

Artemisinin, the first and last naturally occurring 1, 2, 4-trioxane originated from Artemisia annua, L. and its derivatives are a potent class of antimalarial drugs. The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and it is high in such areas as well where multidrug-resistance is rampant. Furthermore, artemisinin and many of its analog possess not only antiparasitic effect against Plasmodium falciparum, Schistosoma japonicum and Clonorchis sinensi but also immuno-modulation effects, and antitumor activities. This review covers the chemistry of artemisinin including synthesis of acetal-, non acetal-type C-12 analogs, C-11- and C-13 derivatives from artemisitene, ring-contracted derivatives, dimers, and trimers. Modes of biological action of artemisinin - derived analogs are also reviewed. The main objective of this article is to review the literatures of recent progress taken place in chemistry, mode of biological actions of artemisinin, and its derivatives as antimalarial and antitumor agents during the last three years (1999-2001).     

冬凌草甲素抗肿瘤的研究进展

冬凌草甲素是从冬凌草等植物中提取出的一种贝壳杉烯二萜类化合物,在抑制肿瘤细胞增殖、诱导自噬及凋亡等方面具有较好的抗肿瘤活性。本文对冬凌草甲素的抗肿瘤活性及作用机制的研究进展作一综述。     

青蒿素类衍生物抗炎免疫抑制活性研究进展

青蒿素类衍生物具有抗炎和免疫抑制活性。临床研究结果表明,青蒿素类衍生物对各类红斑狼疮、皮炎及关节炎有效;研究表明,青蒿素类衍生物在多种疾病动物模型上具有抗炎和免疫抑制活性。为了研究和获得免疫抑制活性更高的化合物,一系列经过结构改造后合成的新型青蒿素类化合物相继被报道。但到目前为止,有关青蒿素类衍生物免疫抑制活性的作用机制尚不清楚。本文主要综述了近年来青蒿素类衍生物抗炎和免疫抑制药理作用及其作用机制的研究进展。     

用比较分子力场分析法研究青蒿素醚类和酯类衍生物的三维定量结构—活性关系(英文)

运用三维定量结构—活性关系分析方法—比较分子力场分析法(CoMFA),研究了青蒿素醚类和酯类衍生物的理化性质与抗疟活性的关系。选用的四种分子重叠模型,其计算结果均有较强的预测能力,其中模型B得到的分子立体场分布与Avery等的实验结果一致;模型A、B和C的静电场分布计算结果与我们的量子化学计算结果一致;模型D的预测结果表明,—C_6-O_2-O_1-C_(10)-O_3-C_7-O_4-C_(12)-O_5-和C_(16)是抗疟活性的重要基团。     

The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents

Artemisinin derivatives such as artesunate, dihydroartemisinin and artemether are playing an increasing role in the treatment of drug-resistant malaria. They are the most potent antimalarials available, rapidly killing all asexual stages of the parasite Plasmodium falciparum. This review highlights the recent developments in the area of improved second-generation semi-synthetic artemisinin derivatives and fully synthetic antimalarial endoperoxide drugs. In pursuit of synthetic analogues of the artemisinins, one of the major challenges for chemists in this area has been the non-trivial development of techniques for the introduction of the peroxide bridge into candidate drugs. Although chemical research has enabled chemists to incorporate the endoperoxide ‘warhead’ into synthetic analogues of artemisinin, significant drawbacks with many candidates have included comparatively poor antimalarial activity, non-stereoselective syntheses and chemical approaches that are not readily amenable to scale up. However, very recent progress with synthetic 1,2,4-trioxolanes provides a new benchmark for future medicinal chemistry efforts in this area.     

Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin

Objectives The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains. Methods The ethers were synthesized in a one‐step process by coupling ethylene glycol moieties of various chain lengths to carbon C‐10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine‐sensitive (D10) and moderately chloroquine‐resistant (Dd2) strains of P. falciparum. Key findings The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8 , featuring three ethylene oxide units, was the most active of all the synthesized ethers. Conclusions The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water‐soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water‐soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length.     

Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin

PURPOSE: To characterize artemisinin pharmacokinetics (PK) and its antimalarial activity in vivo. METHODS: Artemisinin salivary concentration and parasite count data were obtained from Vietnamese malaria patients receiving two different dosage regimens. PK data were analysed using a previously developed semiphysiological model incorporating autoinduction of eliminating enzymes. A pharmacodynamic (PD) model reflecting different stages of the parasite life-cycle was developed and fitted to the data. The model included visible and invisible compartments as well as sensitive, insensitive, and injured parasite stages. Salivary artemisinin concentrations functioned as the driving force for the observed decrease in the number of parasites. RESULTS: Large interindividual variability was observed in both PK and PD data. The PK model described reasonably well the observed decrease in salivary concentrations after repeated drug administration. The preinduction hepatic extraction ratio of artemisinin was estimated to be 0.87 with a volume of distribution of 27 L. Artemisinin half-life averaged 0.7 h. Incorporation of a saturable hepatic elimination affecting the first-pass extraction as well as a higher intrinsic clearance in female patients resulted in the best fit of the model to the data. The PD model described the decrease in the number of parasites during the course of treatment well. The longest mean transit time of parasites from sensitive, visible to invisible to insensitive visible stages was found to be 34.5 h through one life-cycle. The half-life of injured parasites was 2.7 h. CONCLUSIONS: The proposed semimechanistic PK/PD model successfully described the time course of both salivary artemisinin concentrations after repeated dosing and the number of parasites in patients treated with the drug.     

青蒿素类抗疟药的作用机制及耐药机制研究进展

青蒿素及其衍生物是一类全新结构的抗疟药，具有抗疟作用迅速、高效、低毒且与大多数抗疟药无交叉抗性等特点。一般认为，青蒿素类药物的作用机制与其结构中的内过氧桥有关，最近又提出一些与以往不同的观点。治疗疟疾的其他药物如氯喹、甲氟喹、乙胺嘧啶等在治疗疟疾的过程中均已产生耐药性，而青蒿素类药物由于其独特的化学结构，是至今唯一没有出现耐药性的抗疟药，因此确定其作用机制，对避免其耐药性的产生，延长其使用寿命具有重要意义。