Structural basis of anthracycline selectivity for unilamellar phosphatidylcholine vesicles: an equilibrium binding study.
Structural basis of anthracycline selectivity for unilamellar phosphatidylcholine vesicles: an equilibrium binding study.
复制标题
单层磷脂酰胆碱囊泡的蒽环类药物选择性的结构基础：平衡结合研究。
DOI：
10.1021/bi00328a030
复制
发表时间：
1985
期刊：
影响因子：
2.9
通讯作者：
Tritton,TR
中科院分区：
文献类型：
--
作者：
Burke,TG;Tritton,TR
耶鲁大学医学院药理学系，New Haven，Connecticut 06510，和佛蒙特大学医学院药理学系，Burlington，Vermont 05405接收日期：1984年8月15日摘要：用荧光各向异性滴定法测定了几种蒽环类抗肿瘤抗生素与二肉豆蔻酰磷脂酰胆碱（DMPC）的平衡结合亲和力和二棕榈酰磷脂酰胆碱（DPPC）囊泡。八个柔红霉素类似物，所有不同的父母由一个结构变化的糖苷配基部分的分子，以及四个蒽环类同系物的氨基糖进行了研究。双倒数图用于确定总体结合亲和力（K）。结果表明，柔红霉素分子的糖苷配基和氨基糖部分的结构变化强烈调制DMPC和DPPC双层的K值。对于蒽环类药物的糖苷配基部分的修饰，观察到药物疏水性和膜亲和力之间的相关性。在多个温度下测定了阿霉素、道诺霉素和洋红霉素的每个磷脂分子的结合位点数量（）和表观结合常数（Kipp），其中K= nKipp。的n值被发现是独立的温度为流体相DMPC或固相DPPC双层。ifapp值（25 ℃）范围为DMPC囊泡的（0.82-4.4）× 105 M-1至DPPC囊泡的（4.4-7.3）× 105 M-1。尽管三种药物的Kipp值在特定双层中相似，但在n值中观察到了重大差异，因此在总体囊泡亲和力中也存在差异（）。范特霍夫图表明，蒽环类药物结合是放热的，在所有情况下，但一个结合伴随着熵的减少。已发表的蒽环类药物的细胞转运和体外细胞毒性数据似乎与此处测量的K值相关。K值以及热力学参数对药物结构和双层类型的依赖性表明，细胞表面膜可以作为提高蒽环类药物细胞毒性选择性的主要靶点。蒽环类抗肿瘤抗生素是一类重要的用于治疗人类癌症的药物。已经出现了关于蒽环类药物的化学和药理学的大量综述（Arcamone，1981; Young等人，1981; Gianni等人，1983年）。阿霉素是这一系列中使用最广泛的同类物，已被证明会影响细胞膜和模型膜系统的许多性质[参见Tritton和Hickman（1985）的综述]。与阿霉素干扰细胞DNA的能力相比，这些膜变化对阿霉素细胞毒性作用的重要性（被认为是作用机制的经典范例）尚未明确确定。细胞表面膜是阿霉素的主要靶标的最强有力的证据来自聚合物固定化药物的实验（Tritton & Yee，1982; Wingard & Tritton，1983; Wingard等人，1983; Tokes等人，1982; Rogers等人，1983），其中显示非穿透形式的阿霉素比等摩尔浓度的游离药物效力高2-3个数量级。尽管已经证明药物可以仅通过质膜相互作用发挥其生物活性，但更困难的分子机制问题仍未解决。蒽环类抗生素是两亲分子，由一个糖苷配基（一个红色的二羟基蒽醌核）通过糖苷键连接到一个氨基糖组成。
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, and Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont 05405 Received August 15, 1984 abstract: Fluorescence anisotropy titration was used to determine the equilibrium binding affinities of several anthracycline antitumor antibiotics for sonicated dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC) vesicles at 27.5 C. Eight daunomycin analogues, all differing from the parent by one structural change in the aglycon portion of the molecule, as well as four anthracycline congeners modified in the aminosugar were studied. Double-reciprocal plots were used todetermine overall binding affinities (K). It was shown that structural changes in both the aglycon and amino sugar portions of the daunomycin molecule strongly modulated K values for DMPC and DPPC bilayers. For modifications in the aglycon portion of an anthracycline, a correlation between drug hydrophobicity and membrane affinity was observed. The number of binding sites per phospholipid molecule () and the apparent association constant (Kipp), where K= nKipp, were determined at several temperatures for adriamycin, daunomycin, and carminomycin. The n values were found to be independent of temperature for fluid-phase DMPC or solid-phase DPPC bilayers. The ifapp values (25 C) ranged from (0.82-4.4) X 105 M_1 for DMPC vesicles to (4.4-7.3) X 105 M-1 for DPPC vesicles. Although the Kipp values for the three drugs were similar for a particular bilayer, major differences were noted in the values of n and, therefore, in the overall vesicle affinities (). van’t Hoff plots showed that anthracycline binding was exothermic; in all cases but one binding was accompanied by a decrease in entropy. Published data on cellular transport and in vitro cytotoxicities of the anthracyclines appear to correlate with the K values measured here. The dependence of K values as well as thermodynamic parameters on drug structure and bilayer type indicates that the cell surface membrane could serve as a prime target for improving the cytotoxic selectivity of the anthracyclines. e anthracycline antitumor antibiotics are an important class of agents used in the treatment of human cancer. Nu-merous reviews concerning the chemistry and pharmacology of the anthracyclines have appeared (Arcamone, 1981; Young et al., 1981; Gianni et al., 1983). Adriamycin, the most widely used congener of this series, has been shown to influence many properties of cellularmembranes and model membrane systems [see Tritton & Hickman (1985) for a review]. The importance of these membrane changes to the cytotoxic action of adriamycin compared to its ability to interfere with the DNA of the cell, considered the classical paradigmfor the mechanism of action, has not been clearly established. The strongest evidence that the cell surface membrane is a primary target for adriamycin comes from experiments with polymer immobilized drug (Tritton & Yee, 1982; Wingard & Tritton, 1983; Wingard et al., 1983; Tokes et al., 1982; Rogers et al., 1983), where the nonpenetrating form of adriamycin was shown to be 2-3 orders of magnitude more potent than an equimolar concentration of free drug. Although it has been shown that the drug can exert its biological activity solely by a plasma membrane interaction, the more difficult problem of the molecular mechanism remains unsolved. The anthracyclines are amphipathic molecules consisting of an aglycon (a red-pigmented, dihydroxyanthraquinone nucleus) linked through a glycosidic bondto an amino sugar tThis research …