联合应用青蒿素类化合物抗肿瘤研究进展

目的:探讨联合应用青蒿素类化合物抗肿瘤的意义。方法:通过PubMed检索系统搜索近年来国内、外发表的有关青蒿素类化合物联合其他化合物抗肿瘤的文献,对其进行归纳、整理。结果:青蒿素类化合物与多种化合物,如氨乙酸硫酸亚铁、顺铂、卡铂、吉西他滨、环磷酰胺等联合使用,均具有一定的抗肿瘤增效作用。结论:青蒿素类化合物自身毒性小,与多种化合物联合应用具有增效作用,因此研究联合应用青蒿素类化合物抗肿瘤的课题值得关注。     

具有抗微生物活性咔唑类化合物的研究进展

咔唑类化合物是一类重要的芳杂环化合物,在抗细菌、抗真菌和抗病毒方面具有较好的应用前景,深受研究者关注。有关咔唑类化合物的研究包括天然生物碱的分离、全合成、结构修饰及其抗微生物活性研究与开发。本文结合本课题组的研究,综述了近年来咔唑类化合物的抗微生物活性及其构效关系的研究进展。     

鼠曲草的研究进展

鼠曲草所含化学成分主要包括黄酮类化合物、挥发油类化合物和氨基酸类化合物等。现代药理研究证明,鼠曲草具有抗氧化及光防护、抑菌抗炎、保肝等作用。该文从本草考证、化学成分、药理作用等方面就近年来国内外有关鼠曲草的研究进展进行归纳总结,为鼠曲草的深入研究与开发利用提供参考。     

苯并咪唑类酶抑制剂研究进展

苯并咪唑类化合物能对众多酶起到抑制作用,从而产生良好的药理效应。目前,有关苯并咪唑作为酶抑制剂的研究较为活跃,进展迅速,并取得了一系列新的研究成果。此文综述苯并咪唑类化合物在酶抑制剂领域的研究与进展情况。     

柴胡皂苷类化合物体内代谢途径及其代谢产物的研究进展

柴胡皂苷是柴胡中具有生物活性的一类五环三萜类齐墩果烷型衍生物,但因其口服时胃肠道的吸收能力差,生物利用度极低。主要通过对柴胡皂苷类化合物代谢途径及其相关代谢产物进行综述,探讨柴胡皂苷类化合物生物利用度低的原因,并提出柴胡皂苷类化合物发挥药理活性的物质基础可能与其胃肠道转化和催化氧化过程产生的皂苷元结构有关。因此对柴胡皂苷类化合物代谢途径的相关研究,尤其是胃肠道菌群对其的代谢作用研究,能够为临床应用提供更为关键的基础性数据,也具有更为重要的研究价值。     

姜黄素类化合物体内代谢途径及其代谢产物的研究进展

姜黄素类化合物具有明确而广泛的药理作用,但因其溶解度差、结构不稳定,生物利用度极低。主要通过对姜黄素类化合物体内代谢途径及其相关代谢产物进行综述,以明确姜黄素生物利用度低的原因,并提出姜黄素发挥药理活性的物质基础可能与其通过自身氧化和催化氧化过程产生的双环乙酰丙酮结构有关。因此对姜黄素代谢产物进行药动学及相关药效研究,能够为临床应用提供更为关键的基础性数据,也具有更为重要的研究价值。     

丹酚酸类化合物合成研究进展

目的综述丹酚酸类化合物的合成研究进展。方法以国内外有代表性的11篇论文为依据,进行分析、整理和归纳。结果与结论部分丹酚酸类化合物的合成已有文献报道,随着人们对丹酚酸类化合物的合成研究的深入,将会有更多的丹酚酸类化合物被合成。     

香豆素类化合物药理和毒理作用的研究进展

香豆素类化合物是自然界重要的一类天然有机化合物,存在于不同种属的植物中,具有广泛的用途。实验研究发现香豆素具有抗HIV、抗肿瘤、抗氧化、抗炎等多种药理活性,在临床上广泛用于抗凝血和淋巴管性水肿的治疗。近年来的研究发现,香豆素类化合物在啮齿类动物中存在着明显的毒性作用,且具有种属和位点特异性,这与其代谢途径和CYP2A6酶的多态性有关。另外,毒性作用还与给药剂量和给药途径密切相关,口服和高剂量给药更容易产生毒性反应。该文综述了近年来有关香豆素及其衍生物在药理和毒理方面的研究进展,以期为香豆素类化合物的研发和临床应用提供帮助。     

蒽醌类化合物生物活性研究现状与展望

对近年来蒽醌类化合物生物活性研究做一概述,并结合蒽醌类化合物的结构特点和现代配位化学基本理论,提出将稀土金属与蒽醌类化合物组装成配合物的可行性,并对其应用前景进行展望。     

异喹啉类化合物的合成、生物活性与构效关系研究

结合我室异喹啉类化合物心血管活性的研究，主要就双苄基异喹啉类、原小蘖碱共和单苄基异喹啉。类及有关化合物的钙拮抗、③上腺素能ａ、β受体调控、抗心律失常、降压和抗血小板聚集等心血管作用进行了综述。阐述了某些化合物的作用机理和构效关系，还介绍了异喹啉类化合物的三种制备法，     

Recent developments in antitumour taxoids

Since the FDA approval of paclitaxel (Taxol^®, Bristol-Myers Squibb) and docetaxel (Taxotere^®, Rhône-Poulenc Rorer SA, now Aventis) as anticancer drugs, a number of new analogues have been prepared with the view of obtaining taxoids with better potency and bioavailability to targeted cells, as well as taxoids efficient in targeting multi-drug resistant cancer or taxoids acting as modulators of multi-drug resistance (MDR). Studies have also been performed in the search for improved methods in the natural or synthetic preparation of these important anticancer drugs. This review summarises the key aspects of recent patent applications relating to antitumour taxoids that have been published between January 2000 and December 2002. In particular, the review focuses on new processes for the isolation and preparation of antitumour taxoids, new potent taxoids and analogues with improved solubility, as well as taxoid formulation, delivery and association.     

General and recent aspects of the chemistry and structure-activity relationships of taxoids

The antimitotic agents of the Taxoid series are important substances as anticancer drugs. The efficacy of paclitaxel (Taxol) and docetaxel (Taxotere) has been well demonstrated in the treatment of breast, ovarian and lung cancers. Although these drugs have brought benefits in cancer chemotherapy, they unfortunately possess some disadvantages due to their inefficacy on certain resistant cancers, and due to their toxic side effects. For these reasons, the synthesis of new taxoids with improved biological activity is still an important research area. This review while covering general aspects of taxoid chemistry focuses on recent developments in this area especially those contributing to the improved availability of antimitotic taxoids. Studies of structure-activity relationships are also described.     

Design, synthesis, and biological evaluation of new-generation taxoids

Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.     

紫杉烷二萜类化合物精细立体结构研究

抗肿瘤药物紫杉醇(taxol)是一类新型的纺锤体毒药物。已有的关于紫杉醇及其类似物的构效关系研究表明其分子结构中六元A环的C-13侧链与C₄-C₅-C₂₀四元氧环对活性有重要贡献。本文研究了紫杉烷二萜类化合物中5/7/6三环骨架C-4取代方式不同的化合物(4个)及6/8/6三环骨架C-4取代方式不同的3类化合物(10个)的晶体结构,阐述了晶态下紫杉烷二萜类化合物因C-4取代方式不同对分子立体结构的影响,从晶体学角度给出6/8/6/4骨架与抗癌活性的关系。     

Synthesis of novel macrocyclic docetaxel analogues. Influence of their macrocyclic ring size on tubulin activity

This work describes the synthesis of a series of novel macrocyclic taxoids 3 and 3(H) designed to mimic the docetaxel solid-state ("nonpolar") conformation. These compounds, bearing 18-, 20-, 21-, and 22-membered rings connecting the C-2 OH and C-3' NH moieties, were constructed by ring-closing olefin metathesis of the taxoid-omega,omega'-dienes 4. Biological evaluation of these new taxoids showed that activity is dependent on the ring size, and only the 22-membered ring taxoid 3d exhibits significant tubulin binding. Synthesis of the open-chain analogues 7 and 7(H) and comparison of their biological activities with macrocyclic taxoids show that the carbon tether between C-2 OH and C-3' NH does not hamper tubulin binding. Computational studies of the conformational behavior of the macrocyclic taxoids 3 indicate that the 18-, 20-, and 21-membered-ring 3a-c adopt mainly conformations that are not recognized by tubulin. The most active taxoid 3d appears to adopt a conformation that is between the "nonpolar" and T-shaped forms.     

Recent strategies in the development of taxane anticancer drugs

Paclitaxel (Taxol^®, Bristol-Myers Squibb) and docetaxel (Taxtere^®, Rhône-Poulenc Rorer SA - now Aventis), complex polyoxygenated taxane diterpenoids bearing phenylisoserine moieties currently in extensive clinical use for the treatment of breast, ovarian and other cancers, are considered to be two of the most important drugs in cancer chemotherapy. However, low solubility, multi-drug resistance (MDR), dose-limiting toxicity as well as other adverse effects associated with these drugs present significant drawbacks. Accordingly, seeking the solutions to these problems of taxane anticancer drugs has been the main focus of both academic and industrial research activities for the period of 1997 - 1999. New taxoids (i.e., Taxol^®-like compounds) with various modifications at the baccatin skeleton and the phenylisoserine side chain have been developed, which possess improved potency, especially against cancers expressing P-glycoprotein (P-gp)-based MDR. A number of prodrugs of paclitaxel and taxoids have been designed and synthesised to tackle the solubility problem, mainly by attaching water-soluble subunit(s) to the C-2 and/or C-7 hydroxyl groups. Novel tumour-recognising taxoids and taxane-based MDR modulators have also been developed, showing considerable promise. Recently, the improvement in drug formulation and delivery of taxane anticancer agents has been receiving increasing attention.     

Recent progress in the development of docetaxel and paclitaxel analogues

Docetaxel (Taxotere^®, Sanofi-Aventis) and paclitaxel (Taxol^®, Bristol-Myers Squibb) are potent anticancer agents commonly used for the treatment of breast, ovarian and other cancers. Chemotherapy with these compounds gives undesirable side effects due to their low solubility and to the lack of selectivity for cancer cells. Studies have been performed to solve these problems and to find more potent taxoids on drug-resistant cancers. This review summarises the progress in these areas as reported in recent patent applications on docetaxel and paclitaxel analogues that have been published between January 2003 and December 2005. The review specifically focuses on new methods for the production of taxoids, new potent analogues, including taxoid conjugates with improved solubility, tumour targeting taxoids and prodrugs, combinations with new anticancer agents and taxoid formulation and delivery.     

Synthesis and biological evaluation of 2'-methyl taxoids derived from baccatin III and 14beta-OH-baccatin III 1,14-carbonate

A series of 2'-methyl taxoids were synthesized and essayed for growth inhibition experiments conducted in human ovarian cancer cell line A2780wt and its counterparts A2780cis, A2780tax, and A2780adr, resistant to cisplatin, paclitaxel, and doxorubicin, respectively, to test the effect of this substituent on the antitumor activity. Additional experiments were performed on MCF-7 human breast cancer cell line and MCF7-R resistant to doxorubicin. In several cases these taxoids were more active than paclitaxel showing subnanomolar IC(50) values.     

Taxanes in Taxus baccata pollen: cardiotoxicity and/or allergenicity?

Diterpenic alkaloids belonging to taxine (yield: 0.18 % dry weight) and taxoids (paclitaxel, baccatine III and 10-deacetylbaccatine III, cumulated yield: 0.004 % dry weight) were isolated from Taxus baccata L. pollen. Moreover, taxoids conjugated to macromolecules were also detected by ELISA. According to these data and to semi-quantitative measurements of pollen production, a hundred-year-old yew during its flowering time releases several grams of taxanes contained in 16 to 20 kg of pollen. Toxicity assays on mice indicated that any risk of acute toxicity resulting from Taxus pollen inhalation and subsequent taxine absorption is unlikely. On the other hand, anti-paclitaxel IgG were above all detected in sera of subjects displaying hypersensitivity reactions during the pollination periods of Taxus sp. and Betula sp. This natural anti-paclitaxel IgG acquisition by individuals living in the distribution areas of these trees could be at the origin of atopic manifestations. We also postulate that such a natural sensitization could have a marked influence on the tolerance to anticancer taxoids.     

Isolation of taxoids from cell suspension cultures of Taxus wallichiana

Cell suspension cultures of stem-derived callus of Taxus wallichiana in MS-F culture media were found to produce three C-14 oxygenated taxoids and one regular taxoid. The taxoids were identified as yunnanxane (1), 2 alpha, 5 alpha, 10 beta, 14 beta-tetraacetoxy-4(20),11-taxadiene (2), 2 alpha, 5 alpha, 10 beta-triacetoxy-14 beta-(2-methyl)-butyryloxy-4(20),11-taxadiene (3) and 1 beta-hydroxybaccatin I (4).