New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors
| Autor: | Clemens Anklin, Amos B. Smith, Jeffrey D. Serrill, Kerry L. McPhail, Minh H. Nguyen, Jane E. Ishmael, Mohamad Nazari, David A. Gallegos, Xuemei Wan |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Glycosylation
Oligomycin Cellular respiration Cell Survival Apoptosis Oxidative phosphorylation 010402 general chemistry 01 natural sciences Article chemistry.chemical_compound Drug Discovery medicine Humans Glycolysis Cytotoxicity ATP synthase biology 010405 organic chemistry Mitochondrial Proton-Translocating ATPases 0104 chemical sciences Mitochondria HEK293 Cells Biochemistry chemistry Mechanism of action biology.protein Molecular Medicine Macrolides medicine.symptom HeLa Cells |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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