Synthesis and Functional Analysis of Cell Adhesion Inhibitory Polyketides

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Polyketide-derived marine natural product lasonolide A, which was isolated from the shallow water Caribbean marine sponge, Forcepia sp., was shown to inhibit the in vitro proliferation of A-549 human lung carcinoma cells as well as to inhibit cell adhesion in a newly developed whole cell assay that detects signal transduction agents. We planned to synthesize this natural product and to discover a new and efficient lead compounds for the development of new drugs(1 ) Synthesis of the C_1-C_<17> segment : Lasonolide A was divided into three segments. Of these, the C_1-C_<17> segment was prepared enantioselectively(2) Synthesis of the C_<18> C_<25> segment : The C_<18>-C_<25> segment, which is the most difficult segment for the preparation, was enantioselectively synthesized by using the characteristic structural feature of dioxabicyclo [3.2.1] octane chiral building block. The synthetic route is also efficient and flexibe(3) Synthesis of the C_<26>C_<35> segment : The acyclic segment C_<26>-C_<35> was prepared starting from valeraldehyde and (S)-malic acid. Thus the three segments required for the total synthesis of lasonolide A were synthesized successfully. Since the synthetic routes for the segments are efficient and flexible, they would contribute to find useful lead compound for the development of new drugs(4) Biological evaluations of the synthetic intermediates of lasonolide A : To explore the useful lead compounds for the development of new drugs, the biological assay for several kinds of synthetic intermediates of lasonolide A was investigated by using normal cell and some cancer cells. As a result, interestingly, a simple lactone intermediate exhibited cytotoxicity and apoptosis-like activity