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Zampanolides B−E from the Tongan marine sponge Cacospongia mycofijiensis: Potent Cytotoxic Macrolides with Microtubule-Stabilizing Activity Taitusi Taufa* a , A. Jonathan Singh d,e , Chloe R. Harland b , Vimal Patel c,d , Ben Jones c,d Tu′ikolongahau Halafihi f , John H. Miller c,d , Robert A. Keyzers b,d and Peter T. Northcoted d,e a School of Agriculture, Geography, Environment, Ocean and Natural Sciences, The University of the South Pacific, Suva, Laucala Campus b School of Chemical and Physical Sciences, Victoria University of Wellington, New Zealand
c School of Biological Sciences, Victoria University of Wellington, New Zealand d Centre for Biodiscovery, Victoria University of Wellington, New Zealand e Ferrier Research Institute, Victoria University of Wellington, New Zealand f Ministry of Fisheries, Sopu, Tongatapu, Kingdom of Tonga
The islands of the South Pacific Ocean have been in the limelight for bioprospecting, due to their unique and pristine tropical waters and environment. The Kingdom of Tonga is an archipelago in the South Pacific Ocean, consisting of 176 islands, of which 53 are inhabited, flourishing with a rich biodiversity of flora and fauna. Many unique natural products with interesting biological activities have been reported from South Pacific marine organisms; however, there have been limited studies on Tongan organisms compare to other small Pacific Island nations. A NMR-directed investigation of the Tongan marine sponge Cacospongia mycofijiensis has resulted in the isolation of four new compounds (2−5) structurally related to the microtubule-stabilizing agent (−)-zampanolide (1). 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 Δ8, the configuration of this alkene and those of Δ4 and Δ4’ have little effect on tubulin polymerization. The first natural co-occurrence of 1 and (−)-dactylolide (6) from the same sponge established a firm conclusion regarding the controversial configuration of dactylolide.
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