During the course of our investigation searching for new bioactive substances from marine organisms, we isolated an extremely potent cytotoxic polyketide designated callystatin A (1) from the marine sponge Callyspongia truncata and determined its absolute stereostructure. In order to create a new anti-tumor lead compound, the structure-activity relationships of 1 using several synthetic analogues have been studied. As a result of evaluating their cytotoxicities, the following crucial factors have been disclosed; 1) α, β-unsaturated δ-lactone moiety is a conclusive pharmacophore; 2) 5-R configuration, asymmetric center at C-10, and β-hydroxy ketone moiety contribute to affinity to receptor molecule. From the experiment utilizing the fission yeast expressing an NES-GFP-NLS fusion protein, callystatin A (1) was found to inhibit nuclear export signals (NES) dependent transport of proteins from the nucleus to the cytoplasm as well as leptomycin B (2). In addition, 1 was shown to inhibit direct binding between NES and CRM1 through the competitive experiment by use of the biotinylated leptomycin B.
