Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide.
Leucascandrolide A and neopeltolide are structurally homologous marine natural products that elicit potent antiproliferative profiles in mammalian cells and yeast. The scarcity of naturally available material has been a significant barrier to their biochemical and pharmacological evaluation. We developed practical synthetic access to this class of natural products that enabled the determination of their mechanism of action. We demonstrated effective cellular growth inhibition in yeast, which was substantially enhanced by substituting glucose with galactose or glycerol. These results, along with genetic analysis of determinants of drug sensitivity, suggested that leucascandrolide A and neopeltolide may inhibit mitochondrial ATP synthesis. Evaluation of the activity of the four mitochondrial electron transport chain complexes in yeast and mammalian cells revealed cytochrome bc(1) complex as the principal cellular target. This result provided the molecular basis for the potent antiproliferative activity of this class of marine macrolides, thus identifying them as new biochemical tools for investigation of eukaryotic energy metabolism.
Ulanovskaya
Olesya A
OA
Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
Janjic
Jelena
J
Suzuki
Masato
M
Sabharwal
Simran S
SS
Schumacker
Paul T
PT
Kron
Stephen J
SJ
Kozmin
Sergey A
SA
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D018942:Macrolides; D012717:Sesquiterpenes; C408748:leucascandrolide A; C519136:neopeltolide; D014450:Electron Transport Complex III