Chemistry and structure activity relationships of bafilomycin A(1), a potent and selective inhibitor of the vacuolar H+-ATPase

Bafilomycin A(1), a macrolide antibiotic isolated from the fermentation of Streptomyces spp., is a potent and selective inhibitor of vacuolar-type pro ton translocating ATP-ases (V-ATPases) and was used to study the physiologi cal role of this class of enzymes. An extensive chemical effort on the unus ual structure of this macrolide led to the synthesis of significantly diffe rent bafilomycin derivatives. None of the new analogues was more potent tha n the parent compound but provided a significant amount of information abou t the structural requirements for the inhibitory activity of bafilomycin A( 1) in particular on chicken osteoclast (cOc) ATPase. The vinylic methoxy gr oup adjacent to a carbonyl function, the dienic system and the hydroxy grou p at position 7 were recognized to be essential features for bafilomycin V- ATPase-inhibitory activity. This information was utilized to design simplif ied novel derivatives as inhibitors of bone resorption.