New Mandelalides Expand a Macrolide Series of Mitochondria! Inhibitors

作者：Nazari Mohamad; Serrill Jeffrey D; Wan Xuemei; Nguyen Minh H; Anklin Clemens; Gallegos David A; Smith Amos B III; Ishmael Jane E; McPhail Kerry L

来源：Journal of Medicinal Chemistry, 2017, 60(18): 7850-7862.

DOI：10.1021/acs.jmedchem.7b00990

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.

• 出版日期2017-9-28