Studies on the stereochemistry of new macrolides from marine organisms for research and development of drug molecules

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In this research project, we investigated on determination of absolute stereochemistry of many chiral centers contained in bioactive marine natural products classified as macrolides, which were isolated from marine sponges and dinoflagellates by our research group.1.Theonezolide A is a novel cytotoxic 37-membered macrolide isolated from the Okinawan marine sponge Theonella sp., having unique bioactivity of induction of rabbit platelet shape change and aggregation. Theonezolide A contains 23 chiral centers, among which the absolute configuration of one chiral center at the terminal position (C-75) was determined as R on the basis of synthesis of a degradation product. As to the C-4-C-17 fragment, which was obtained by ozonolysis of the macrolide, the relative configurations of two 1,3-diol type moieties were suggested as both syn from the synthesis of model compounds. Four structures therefore remained to be likely, and two possible diastereomers were synthesized as optically active forms. Comparison of their spectral and optical data established the absolute configuration of four chiral centers contained in the C-4-C-17 fragment as 8S,10R,14S,16S.2.Amphidinolides are unique macrolides obtained from cultured marine dinoflagellate Amphidinium sp. A diastereomer of the C-1-C-9 fragment of amphidinolide C,one of the potent cytotoxic macrolides isolated from this dinoflagellate, was synthesized to provide an authentic sample for the degradation studies. To provide an adequate quantity of the natural product to supply for degradation experiments, further large-scale culturing of the dinoflagellate Amphidinium sp.was continued. During further examinations on the extracts of the cultured cells of this dinoflagellate, two new macrolides, amphidinolides R and S,were isolated and their structures including absolute configuration were elucidated on the basis of spectroscopic data as well as chemical experiments.