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.

Hygrobafilomycin, a cytotoxic and antifungal macrolide bearing a unique monoalkylmaleic anhydride moiety, from Streptomyces varsoviensis

“…The number of methyl groups, 10 for compound 6 and 9 for most bafilomycins suggest that 1 methoxy group, likely at C-2, is replaced by a methyl group. This was confirmed by the 13 Figure 3). Second, compared with 2, 15 compound 6 possesses three additional ethylenic carbons, one quaternary sp 2 carbon and three ester carbonyl groups.…”

“…The lower cytotoxic activity of compound 3 (mean IC 50 86.3 nM) points to a crucial role of the tetrahydropyran ring system, as this was found for the vacuolar ATPase inhibition effect of bafilomycin derivatives. 13 A particular importance of the maleic anhydride moiety, as found in other cases, could not be connoted. 19 As the compounds show only low cell line selectivities, a basic physiological function as cellular target seems plausible.…”

“…However, the practical use of these macrolides has been limited because of fatal toxicity, 12 thus propelling semi-synthetic and biosynthetic engineering programs with the aim to create novel derivatives with better efficacy. 13,14 In this study, we report the isolation and structure characterization of a cytotoxic antifungal bafilomycin-hygrolidin hybrid, named hygrobafilomycin (6), featuring an unprecedented monoalkylmaleic anhydride moiety, and its biological evaluation using a panel of tumor cell lines.…”

Iejimalides Show Anti-Osteoclast ActivityviaV-ATPase Inhibition

“…1). 27,28) These features are conserved in most bafilomycins, concanamycins, and chondropsins, which recently were identified as novel types of V-ATPase inhibitors. 29) Interestingly, IEJLs do not have these structural features, except for dienic systems, which are frequently observed in macrolides.…”

Inhibitors of V-ATPases: old and new players

“…1) in the early 1980s (Kinashi et al, 1982;Kinashi et al, 1984;Werner et al, 1984). The structure-activity relationship for bafilomycin and concanamycin was investigated intensively (Dröse and Altendorf, 1997;Dröse et al, 1993;Dröse et al, 2001;Gagliardi et al, 1998a;Gagliardi et al, 1999). However, for more than a decade the location of the binding site in the enzyme was not known.…”