title: Synthesis and structure-activity relationships of bafilomycin A1 derivatives as inhibitors of vacuolar H+-ATPase.
abstract: The macrolide antibiotic bafilomycin A1 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 A1 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 A1. 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.
authors.affiliation: SmithKline Beecham SpA, Via Zambeletti, 20021 Baranzate, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Gagliardi
authors.forename: P A
authors.initials: PA
authors.lastname: Gatti
authors.forename: P
authors.initials: P
authors.lastname: Belfiore
authors.forename: A
authors.initials: A
authors.lastname: Zocchetti
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: C
authors.initials: C
authors.lastname: Farina
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000313:Adrenal Medulla / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D002645:Chickens; D019439:Chromaffin Cells / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D017494:Proton Pumps / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014617:Vacuoles / Q000201:enzymology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; D017494:Proton Pumps; C040929:bafilomycin A1; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases