Zampanolides B–E from the Marine Sponge Cacospongia mycofijiensis : Potent Cytotoxic Macrolides with Microtubule-Stabilizing Activity

Four new compounds ( 2 – 5 ) structurally related to the microtubule-stabilizing agent (−)-zampanolide ( 1 ) have been isolated from the Tongan marine sponge Cacospongia mycofijiensis . Three of these new structures, zampanolides B–D ( 2 – 4 ), exhibit nanomolar cytotoxicity toward the HL-60 cell line, are antimitotic, and induce in vitro tubulin polymerization at levels comparable to 1 . Zampanolide E ( 5 ), saturated at C-8/C-9, was significantly less potent and does not stabilize purified tubulin, even at 10-fold higher concentrations. The structural differences across these compounds reveal a plasticity of the zampanolide pharmacophore. While unsaturation is required at Δ 8, the configuration of this alkene and those of Δ 4 and Δ 4′ have little effect on tubulin polymerization. The first natural co-occurrence of 1 and (−)-dactylolide ( 6 ) from the same sponge extract is also noted.