New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors

Mandelalides A–D (1–4)
are macrocyclic polyketides known to have an unusual bioactivity profile
influenced by compound glycosylation and growth phase of cultured
cells. The isolation and characterization of additional natural congeners,
mandelalides E–L (5–12), and
the supply of synthetic compounds 1 and 12, as well as seco-mandelalide A methyl ester (13), have now facilitated mechanism of action and structure–activity
relationship studies. Glycosylated mandelalides are effective inhibitors
of aerobic respiration in living cells. Macrolides 1 and 2 inhibit mitochondrial function similar to oligomycin A and
apoptolidin A, selective inhibitors of the mammalian ATP synthase
(complex V). 1 inhibits ATP synthase activity from isolated
mitochondria and triggers caspase-dependent apoptosis in HeLa cells,
which are more sensitive to inhibition by 1 in the presence
of the glycolysis inhibitor 2-deoxyglucose. Thus, mandelalide cytotoxicity
depends on basal metabolic phenotype; cells with an oxidative phenotype
are most likely to be inhibited by the mandelalides.