Synthesis and structure-activity relationships of bafilomycin A1 derivatives as inhibitors of vacuolar H+-ATPase

被引：65

作者：

Gagliardi, S ^{[1
]}

Gatti, PA ^{[1
]}

Belfiore, P ^{[1
]}

Zocchetti, A ^{[1
]}

Clarke, GD ^{[1
]}

Farina, C ^{[1
]}

机构：

[1] Smithkline Beecham SpA, I-20021 Milan, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 11期

关键词：

D O I：

10.1021/jm9707838

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The macrolide antibiotic bafilomycin A(1) is a highly potent and selective inhibitor of all the vacuolar ATPases (V-ATPases). With the aim of obtaining novel analogues specific for the osteoclast subclass of vacuolar ATPase, 31 derivatives of bafilomycin A(1) were synthesized and tested for their ability to inhibit differentially the V-ATPase-driven proton transport in membrane vesicles derived from chicken osteoclasts (cOc) and bovine chromaffin granules (bCG). Although none of the new analogues were more potent than the parent compound, the obtained data provided a significant amount of information about the structural requirements for the inhibitory activity of bafilomycin A(1). The different effects of a few analogues on the two enzymes could also suggest the possibility of a selective modulation of the V-ATPases in different tissues.

引用

页码：1883 / 1893

页数：11

共 31 条

[1] A CONFORMATIONAL STUDY OF BAFILOMYCIN-A1 BY X-RAY CRYSTALLOGRAPHY AND NMR TECHNIQUES [J].