描述了由9种S-氨基酸和R-乳酸组成的新型抗真菌环肽1的一系列衍生物的合成。除了MeAsp4(酯2a-d,酰胺3a-d,醇4及其衍生物)和Tyr(Me)9(脱甲基衍生物8,醚12a-f,13)的官能团变化以及苯基被氧化降解为14),通过LiOH在THF / H 2 O中打开内酯允许操纵所得无环肽15中R-Hypr10的羟基。在Mitsunobu条件下将15环化,然后脱保护,得到1的S-Hypr10类似物17。通过相应的修饰的线性肽23、24、27和28通过环化获得环状十肽33和34以及环状十一肽35和36。
Derivatives of a Novel Cyclopeptolide. 2. Synthesis, Activity against Multidrug Resistance in CHO and KB Cells in vitro, and Structure-Activity Relationships
摘要:
A series of derivatives of the novel cyclopeptolide 1 was prepared, and their ability to chemosensitize multi drug resistant CHO and KB cells in vitro was evaluated. In contrast to the parent compound, several of the derivatives were found to be highly active. In particular, conversion of the R-lactic acid residue of 1 into its S-isomer via lactone ring cleavage and recyclization with inversion resulted in a marked enhancement of activity. Some of these derivatives (e.g., 15a, SDZ 280.446) belong to the most potent resistance modulating compounds known so far.