Correlation of F0F1-ATPase inhibition and antiproliferative activity of apoptolidin analogues.
[structure: see text] Apoptolidin (1) exhibits potent and highly selective apoptosis inducing activity against sensitive cancer cell lines and is hypothesized to act by inhibition of mitochondrial F(0)F(1)-ATP synthase. A series of apoptolidin derivatives, including a new intermolecular Diels-Alder adduct, were analyzed for antiproliferative activity in E1A-transformed rat fibroblasts. Potent F(0)F(1)-ATPase inhibition was not a sufficient determinant of antiproliferative activity for several analogues, suggesting the existence of a secondary biological target or more complex mode of action for apoptolidin.
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA. wenderp@stanford.edu
Paul A
PA
Wender
Orion D
OD
Jankowski
Kate
K
Longcore
Elie A
EA
Tabet
Haruo
H
Seto
Taijiro
T
Tomikawa
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D051381:Rats; D014407:Tumor Cells, Cultured; D015003:Yeasts / Q000201:enzymology
D000970:Antineoplastic Agents; D018942:Macrolides; D006180:Proton-Translocating ATPases; C114125:apoptolidin