Correlation of F0F1-ATPase inhibition and antiproliferative activity of apoptolidin analogues

Apoptolidin (1) exhibits potent and highly selective apoptosis inducing activity against sensitive cancer cell lines and is hypothesized to act by inhibition of mitochondrial F0F1-ATP synthase. A series of apoptolidin derivatives, including a new intermolecular Diels-Alder adduct, were analyzed for anti proliferative activity in ESA-transformed rat fibroblasts. Potent F0F1-ATPase inhibition was not a sufficient determinant of anti proliferative activity for several analogues, suggesting the existence of a secondary biological target or more complex mode of action for apoptolidin.