A new approach to (+)-cacospongionolide was developed to access conformationally restricted variantsof the natural product. The flexible aliphatic region between the decalin and side chain portion of thenatural product was replaced with alkenyl and alkynyl linkers to probe the influence of structural rigidityin the inhibition of secretary phospholipase A
2 (
sPLA
2). It was found that when the aliphatic section isreplaced with a
Z-olefin or an alkyne,
sPLA
2 inhibitory activity suffered relative to the natural product;however, an
E-olefin-containing analogue led to an enhanced activity. These results suggest that preferred
sPLA
2 binding conformation of the natural product is similar to the geometry of the
E-olefin-containinganalogue.