SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF BAFILOMYCIN A(1) DERIVATIVES AS INHIBITORS OF VACUOLAR H-ATPASE()

The macrolide antibiotic bafilomycin A(1) is a highly potent and selec tive inhibitor of all the vacuolar ATPases (V-ATPases). With the aim o f obtaining novel analogues specific for the osteoclast subclass of va cuolar ATPase, 31 derivatives of bafilomycin A(1) were synthesized and tested for their ability to inhibit differentially the V-ATPase-drive n proton transport in membrane vesicles derived from chicken osteoclas ts (cOc) and bovine chromaffin granules (bCG). Although none of the ne w analogues were more potent than the parent compound, the obtained da ta provided a significant amount of information about the structural r equirements for the inhibitory activity of bafilomycin A(1). The diffe rent effects of a few analogues on the two enzymes could also suggest the possibility of a selective modulation of the V-ATPases in differen t tissues.