阿司匹林衍生物药理活性研究概述

阿司匹林具有多种药理活性,是老药新用的典型药物之一。近年来,人们为开发阿司匹林,对其结构进行修饰及改造,以期得到副作用更小、活性更好的衍生物。本文总结了30种阿司匹林衍生物的合成路线及药理活性。其药理活性主要集中在解热镇痛、抗炎、抗骨质疏松、防治心脑血管疾病及抗肿瘤活性等方面,可为相关研究和应用提供参考。     

长春花化学成分和药理作用研究进展

长春花属植物是原产于非洲东海岸的野生花卉,现已广泛分布于世界各地.长春花含有萜类生物碱、二聚吲哚生物碱、单吲哚生物碱等多种生物碱类活性成分和黄酮类成分.近年来长春花中单体成分或结构修饰物作为药物被广泛用于治疗多种癌症、糖尿病、高血压及何杰金氏病.综述了近年来对长春花生物碱类和药理活性的研究进展,为更好地开发、利用长春花...     

日本抗癌新药临床前及临床研究进展

通过分子和生化药理学研究已鉴别出许多抗癌药物的新分子靶，微管被认为是癌症化疗的重要的分子靶之一，作用于微管的药物可分为两类：紫杉烷类及长春花生物碱类，前者促进 微管的聚合并提高其稳定性，后者及ｒｈｉｚｏｘｉｎ则抑制微管的聚合，两类生物碱均干扰微的功能。     

抗癌新药诺维本的作用

诺维本(Navelbine,NVB)系法国皮尔法伯药厂生产的新型抗癌生物碱,是继长春花酰碱后又一半合成长春碱类药物。化学名为5＇-去甲去氢长春碱,中文名为异长春花碱(Vinovelbine)。与其它长春碱类药物相比,卡兰它丁环结构发生了改变,9环失去一碳成为8环,从而减弱其神经毒性,成为新一代的长春碱类药物。近年来它在临床上的应用日益受到医生和病人的欢迎。1 作用机理     

抗肿瘤药物长春氟宁

长春氟宁为第3代长春花生物碱双氟化半合成衍生物,对包括尿路上皮移行细胞癌（TCCU）在内的多种实体瘤有抗癌活性,且与其他长春花生物碱衍生物相比,其抗癌活性更强、更安全。一项Ⅲ期临床研究的多因素分析显示：在最佳支持疗法（BSC）的基础上加用长春氟宁能明显提高TCCU患者总体生存率。     

GC-MS分析长春花中的主要吲哚生物碱

在80年代,大量的研究致力于以细胞和组织培养的方法生产长春花中具有药物作用的吲哚生物碱,研究的主要目标是长春新碱和长春碱,它们被用于癌症化疗并作为一些半合成衍生物的前体。上述双吲哚生物碱是由长春花碱(catharanthine)和文朵灵(vindo-line)生物合成的。此外长春花还含有柯南类生物碱阿吗里新(ajmalicine)。由于商业上提供的熔融石英毛细管气相色谱柱固定相有广泛的选择余地.大大扩展了GC分析包括胺和生物碱类在内的不同药物和天然化合物的应用范围。本文研究了以GC-MS方法,通过简单的纯化步骤,同时直接测定长春花中的文朵灵     

近年喹诺酮的结构修饰及药理活性研究进展

喹诺酮类药物经过近50年的发展已成为一大类广泛用于临床的广谱、高效、低毒性的抗感染化疗药物.其中的某些品种被作为二线抗结核病(TB)药物,在治疗耐多药TB以及对不能耐受一线抗TB药物的患者使用中发挥着重要作用.然而,随着它们的广泛使用,甚至滥用,其耐药性迅速增加,故对其结构进行进一步修饰,以期获得活性更强,活性谱更广的新喹诺酮类抗菌药仍是目前的研究热点之一.本文按1-位的结构修饰及抗分枝杆菌活性、2-位的结构修饰及抗肿瘤活性、6-位的结构修饰及药理活性、7-位的结构修饰及药理活性以及喹诺酮杂合物和二聚体及抗菌活性等5个部分比较系统地综述了近年来喹诺酮结构修饰及其药理活性的研究进展.     

喜树碱结构修饰与构效关系研究进展

喜树碱是从喜树提取物中分离出的能够抗细胞增殖的天然生物碱。由于其溶解性低、稳定性差和显著的不良反应限制了其临床应用,所以在过去的十余年里合成了许多喜树碱衍生物。通过引入极性基团、靶向剂或药效团拼合、前药等在喹啉环、5位和20位进行结构修饰,其中大多数与喜树碱相比显示出更强的效力,对不同的肿瘤细胞具有活性,其中许多对多药耐药肿瘤细胞具有活性。综述了近年来47个新的喜树碱衍生物的合成方法和生物活性,并总结了构效关系,发现在喹啉环和内酯环的羟基上修饰通常可以增强体外抗肿瘤活性,药物递送系统、计算机高通量筛选等新技术的应用为改善喜树碱的溶解性、稳定性,寻找活性较好的先导化合物拓展了新思路。     

具有促微管聚合活性的抗肿瘤天然化合物

微管和微管蛋白的相互作用是靶向性筛选抗肿瘤化合物的重要模型之一。化合物与微管蛋白的作用导致两种结果:抑制微管聚合(促解聚)和抑制微管解聚(促聚合)。有许多化合物能与微管蛋白发生作用,其中大多数是降低微管结构稳定性的,如生物碱类的长春碱(ｖｉｎｂｌａｓｔｉｎｅ)、秋水仙碱(ｃｏｌｃｈｉｃｉｎｅ)、喜树碱(ｃａｍｐｔｏｔｈｅｃｉｎ)、ｃｏｍｂｒｅｔａｓｔａｔｉｎ,脂类的ｃｕｒａｃｉｎＡ,大环多醚类的ｈａｌｉｃｈｏｎｄｒｉｎＢ,肽类ｄｏｌａｓｔａｔｉｎ10、ｄｏｌａｓｔａｔｉｎ15、ｈｅｍｉａｓｔｅｒｌｉｎ等;而目前临床…     

4-去乙酰化长春碱氨基酸衍生物的合成

目的:合成4-去乙酰化长春碱氨基酸衍生物,为长春碱靶向前药的合成奠定基础。方法:氨基酸N端采用苄氧羰基(Z)保护,利用混合酸酐法合成(4-去乙酰化长春碱)-氨基酸-Z,然后催化氢化得到(4-去乙酰化长春碱)-氨基酸衍生物。结果:采用新方法合成4-去乙酰化长春碱氨基酸衍生物,结构经质谱和1H-NMR确证。结论:本实验所采用的方法通用性强,优化了反应条件,反应步骤缩短,产率高,产物后处理简便,降低了实验成本。     

Quantitative spectrophotometric determination of alkaloids in roots of Vinca herbacea

A new spectrophotometric method has been developed for the quantitative determination of pharmacologically active alkaloids (maydine, reserpinine, kopsinine, tabersonine, norfluorocurarine) and their sum in roots of Vinca herbacea Walds. et Kit. The proposed technique is highly reproducible and adequately reflects the content of alkaloids in the roots and preparations of Vinca herbacea, which allows this method to be used for their standardization.     

Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells

Multidrug resistance (MDR), typified by resistance to Vinca alkaloids and anthracyclines, is a well characterized experimental phenomenon that may have some clinical correlates. Verapamil, chloroquine, and related drugs have been shown previously to be capable of enhancing anticancer drug cytotoxicity in multi-drug-resistant cells, but the mechanism(s) by which these agents do this is(are) unclear. Since these agents did not seem to have common features, we studied these and other compounds for their ability to "modulate" Vinca alkaloid resistance in order to determine whether they possessed any common chemical or physical features. In addition to verapamil, 24 compounds, consisting of indole alkaloids, lysosomotropic agents, and amines, were tested for their ability to enhance the cytotoxicity of vinblastine and/or vincristine in our human leukemic multidrug-resistant cell line, CEM/VLB100. Seventeen compounds that enhance the cytotoxicity of the Vinca alkaloids by more than 5-fold have been identified. These include quinolines (chloroquine, quinine, chinchonidine, and primaquine), acridines (acridine, acridine orange, and quinacrine), and indole alkaloids (yohimbine, corynanthine, reserpine, physostigmine, and the vindoline and catharanthine moieties of the Vinca alkaloids), as well as other alkaloids and amines (chlorpromazine, propranolol, atropine, and tryptamine). Vindoline, catharanthine, and quinacrine also enhanced the cytotoxicity of doxorubicin and teniposide in these cells, indicating that this "modulation" was not limited to Vinca alkaloids. We examined some well known lysosomotropic compounds (methylamine, epinephrine, suramin, and trypan blue) and found that they were not able to enhance the cytotoxicity of vincristine in the CEM/VLB100 cells, indicating that lysosomotropic activity per se is not required for modulator activity. Three-dimensional computer modeling permitted molecular comparisons of conformationally related congeners of vinblastine, vindoline, and verapamil and revealed three regions of structural homology. We measured the hydrophobicity (by oil/water partitioning) and calculated the molar refractivity (by the additive substituent constant method) of active and inactive compounds. We found that those cationic agents--verapamil, quinacrine, indole alkaloids, and quinolines--that were lipid soluble at physiologic pH and had similar molar refractivities were best able to enhance the cytotoxicity of the Vinca alkaloids in our multidrug-resistant cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Novel aspects of natural and modified vinca alkaloids

The clinical interest of Vinca alkaloids was clearly identified as early as 1965 and so this class of compounds has been used as anticancer agents for more than 30 years. Today, two natural compounds, vinblastine and vincristine and two semi-synthetic derivatives, vindesine and vinorelbine, have been registered and thus Vinca alkaloids can be considered to represent a chemical class of definite utility in cancer chemotherapy. Today, relatively few groups actively research in the chemistry of Vinca alkaloids. However, using superacidic chemistry, a new family of such compounds was synthesised and vinflunine, a difluorinated derivative, was selected for clinical testing. A consideration of the pharmacological data relating to these new derivatives appears to reveal a lack of any marked correlation between in vitro and in vivo results. Furthermore, structure/activity relationships have failed to assist the chemist in the rational design. Such rational design of new derivatives is limited by the fact that the Vinca binding site(s) on tubulin and the exact mechanism(s) of action of Vinca alkaloids remain unclear. Nevertheless, the preclinical evaluations of the new derivative vinflunine have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identified properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semi-synthetic Vinca alkaloids. Thus, Vinca alkaloids remain a drug family with a continuing interest for future anticancer therapy.     

Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies

Background and Purpose

In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested.

Experimental Approach

Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference.

Key Results

In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics.

Conclusion and Implications

Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug–drug interactions.

Linked Article

This article is commented on by Solary, pp 1555–1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12101     

Biologically active substances from amphibians: preliminary studies on anurans from twenty-one genera of Thailand

Amphibian skin has been the source of a wide variety of biologically active substances, but less than one-third of the known genera of amphibians have been probed for such active substances. Skins of 21 genera of anurans from Thailand have now been investigated for noxious secretions, toxic substances, and alkaloids. Four genera of bufonid toads (Bufo, Ansonia, Leptophryne, Pedostipes) were toxic due to the presence of bufadienolides or bufadienolide-like compounds. Two species of ranid frogs (Rana raniceps, Rana signata) were toxic, perhaps due to the presence of toxic peptide(s). Two species of rhacophorid frogs (Polypedates) were slightly noxious/toxic. One species of microhylid frog (Kaloula pulchra) was noxious. Trace amounts of pumiliotoxin alkaloids were detected in a ranid frog (Limnonectes kuhli). A further 18 species did not exhibit noxious or toxic properties to a significant extent.     

New anti-mitotic drugs with distinct anti-calmodulin activity

Bisindole Vinca alkaloids target microtubule system causing anti-mitotic activity. The problem of their clinical application is the lack of selectivity resulting in toxic side effects. In this paper we review the late history of new bisindole derivatives focusing on KARs recognized as potent anti-cancer drugs with low side effect. KARs, just as other bisindoles, impede microtubule assembly of mitotic spindle, however, they display no anti-calmodulin activity. This new drug family appears to be less potent than vinblastine in vitro systems, but it shows high antitumor efficacy with considerably higher doses being well tolerated in the animal tumor models. 3D data of calmodulin complexed with KAR-2 explain the specificity and unique pharmacology of KAR derivatives.     

Chemically modified cell-penetrating peptides for the delivery of nucleic acids

Short nucleic acids targeting biologically important RNAs and plasmids have been shown to be promising future therapeutics; however, their hydrophilic nature greatly limits their utility in clinics and therefore efficient delivery vectors are greatly needed. Cell-penetrating peptides (CPPs) are relatively short amphipathic and/or cationic peptides that are able to transport various biologically active molecules inside mammalian cells, both in vitro and in vivo, in a seemingly non-toxic fashion. Although CPPs have proved to be appealing drug delivery vehicles, their major limitation in nucleic acid delivery is that most of the internalized peptide-cargo is entrapped in endosomal compartments following endocytosis and the bioavailability is therefore severely reduced. Several groups are working towards overcoming this obstacle and this review highlights the evidence that by introducing chemical modification in CPPs, the bioavailability of delivered nucleic acids increases significantly.     

Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine.

The two second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkaloid. For example, vinblastine strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events. We asked whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. IC(50) values for inhibition of HeLa cell proliferation for vinflunine, vinorelbine, and vinblastine were 18, 1.25, and 0.45 nM, respectively, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (38, 3.8, and 1.1 nM, respectively), indicating that mitotic block is a major contributor to antiproliferative action for all three drugs. Mitotically blocked cells exhibited aberrant spindles, consistent with induction of block by suppression of microtubule dynamics. Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. We also found that the peak intracellular drug concentration at the mitotic IC(50) value was highest for vinflunine (4.2 +/- 0.2 microM), intermediate for vinorelbine (1.3 +/- 0.1 microM), and more than 10-fold lower for vinblastine (130 +/- 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for vinflunine's high efficacy and minimal side effects.     

The phagocytosis of yeast cells by blood monocytes. Effects of therapeutic concentrations of vinca alkaloids

Summary The role of cytoplasmic microtubules in the phagocytosis of yeast cells by blood monocytes was studied by means of therapeutic concentrations of the Vinca alkaloids vincristine, vinblastine, and vindesine.Phagocytosis was measured in a monolayer of glass-adherent monocytes fed with fluorescein-labelled yeast cells.Phagocytosis was composed of two sequential processes, yeast cell adherence to the monocyte and yeast cell engulfment by the monocyte.Monocyte phagocytosis was significantly inhibited by the Vinca alkaloids, mainly due to inhibition of engulfment but probably also due to inhibition of adherence.Since the Vinca alkaloids are microtubule antagonists it is reasonable to assume that monocyte phagocytosis, both adherence and engulfment, are partially microtubule-dependent processes.It is suggested that Vinca alkaloid inhibition of monocyte phagocytosis is of value in the treatment of type II–III autoimmune disorders, such as idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia.     

Biologically Active Alkaloids from Poison Frogs (Dendrobatidae)

Abstract

A total of over one hundred biologically active alkaloids have been characterized in skin extracts from dendrobatid frogs. Five major classes have been defined: The highly toxic batrachotoxins are steroidal alkaloids which prevent interactivation of sodium channels in nerve and muscle. Pumiliotoxin-C class alkaloids are decahydroquinolines which block nicotinic receptor mediated neuromuscular transmission. Histrionicotoxins are spiropiperidines which block chemosensitive channels and potassium channels. The pumiliotoxin-A class alkaloids are 6-alkylidene-indolizidines which facilitate calcium-dependent excitation-contraction and excitation-secretion coupling. The gephyrotoxins are indolizidines and perhydrobenzoindolizidines. Gephyrotoxin is a muscarinic antagonist.