ABSTRACT
In order to overcome the multidrug resistance mediated by P-glycoprotein-like transporters in
Leishmania
spp., we have studied the effects produced by derivatives of the flavanolignan silybin and related compounds lacking the monolignol unit on (i) the affinity of binding to a recombinant C-terminal nucleotide-binding domain of the
L. tropica
P-glycoprotein-like transporter and (ii) the sensitization to daunomycin on promastigote forms of a multidrug-resistant
L. tropica
line overexpressing the transporter. Oxidation of the flavanonol silybin to the corresponding flavonol dehydrosilybin, the presence of the monolignol unit, and the addition of a hydrophobic substituent such as dimethylallyl, especially at position 8 of ring A, considerably increased the binding affinity. The in vitro binding affinity of these compounds for the recombinant cytosolic domain correlated with their modulation of drug resistance phenotype. In particular, 8-(3,3-dimethylallyl)-dehydrosilybin effectively sensitized multidrug-resistant
Leishmania
spp. to daunomycin. The cytosolic domains are therefore attractive targets for the rational design of inhibitors against P-glycoprotein-like transporters.
摘要
为了克服利什曼原虫P-糖蛋白样转运体介导的多药耐药性
利什曼
类转运体介导的多药耐药性,我们研究了黄酮木脂素水飞蓟宾的衍生物和缺乏单木脂素单元的相关化合物对(i)
L. tropica
P 糖蛋白样转运体 C 端核苷酸结合域的亲和力,以及 (ii) 耐多种药物的 L. tropica
L. tropica
系过表达该转运体。黄酮醇水飞蓟宾氧化成相应的黄酮醇脱水水飞蓟宾、单木脂醇单元的存在以及疏水取代基(如二甲基烯丙基)的添加(尤其是在环 A 的第 8 位)都大大提高了结合亲和力。这些化合物与重组细胞质结构域的体外结合亲和力与它们对抗药性表型的调节有关。特别是,8-(3,3-二甲基烯丙基)-脱氢水飞蓟宾有效地敏化了耐多药的
利什曼
对戴诺霉素的敏感性。因此,细胞膜结构域是合理设计 P 糖蛋白类转运体抑制剂的诱人靶点。