Design, synthesis, and evaluation of the multidrug resistance-reversing activity of D-glucose mimetics of hapalosin.
Design, synthesis, and evaluation of the multidrug resistance-reversing activity of D-glucose mimetics of hapalosin.
复制标题
Hapalosin D-葡萄糖模拟物的多药耐药逆转活性的设计、合成和评估。
DOI：
10.1021/jm970709p
复制
发表时间：
1998
影响因子：
7.3
通讯作者：
Armstrong,RW
中科院分区：
文献类型：
--
作者：
Dinh,TQ;Smith,CD;Du,X;Armstrong,RW
当5个取代基被置于葡萄糖上时，分子模拟显示，模拟物2和3上的取代基占据与hapalosin上相应取代基相似的空间位置。模拟3及其合成过程中产生的所有吡喃葡萄糖苷中间体逆转P-糖蛋白（P-gp）或多药耐药相关蛋白（MRP）介导的多药耐药（MDR）的能力进行了评估。在使用MCF-7/ADR细胞的细胞毒性和药物蓄积试验中，没有一种糖化合物在抑制P-gp方面像哈巴洛辛一样有效。相比之下，在HL-60/ADR细胞的细胞毒性试验中，四-葡萄糖化合物在拮抗MRP方面表现出与hapalosin相似的功效。
When five substituents of hapalosin were placed ond-glucose, molecular modeling revealed that the substituents on mimetics2and3occupy similar spatial positions as the corresponding substituents on hapalosin. Mimetic3and all the glucopyranoside intermediates generated in its synthesis were assessed for their ability to reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) or the multidrug resistance-associated protein (MRP). None of the sugar compounds were as effective as hapalosin in inhibiting P-gp in cytotoxicity and drug accumulation assays using MCF-7/ADR cells. By contrast, fourd-glucose compounds exhibited similar efficacy as hapalosin in antagonizing MRP in cytotoxicity assays with HL-60/ADR cells.