Studies on the development of drugs for arteriosclerosis based on the inhibition of cell adhesion molecules' induction

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Alkaloid halichlorine, which was isolated from the sponge Halichondria okadai, was shown to inhibit the expression of VCAM-1 (vascular cell adhesion molecule-1), a potential target for the treatment of coronary heart disease and inflammation. Lasonolide A, which is polyene macrolide isolated from the sponge Forcepia sp., was discovered also to inhibit cell adhesion in a newly developed whole cell assay. We planned to synthesize both natural products and to develop a new and efficient drug for the treatment of arteriosclerosis.1. Synthetic studies on halichlorine : The racemic tricyclic core of halichlorine was successfully synthesized by using the tandem intramolecular Michael addition-[3+2] cycloaddition as a key reacton step. For the enantioselective synthesis, the optically active aza-spirocyclic moiety was efficiently constructed.2. Synthetic studies on lasonolide A : Constuctions of the two key structural units, C_1-C_<16> and the C_<18>-C_<25> segments, were investigated. The synthesis of the C_1-C_<16> segment was efficiently accomplished employing the asymmetric epoxidation and alkylation tecniques. On the other hand, the C_<18>-C_<25> segment was synthesized by using a radical cyclization, which was developed by us, as a key step. The synthesized product, however, was the diastereoisomer due to an unexpected epimerization at C_<21> during the conversion.3. Biological evaluations of the synthetic intermediates of halichlorine : To explore the useful lead compounds for the development of new drugs, the biological assay for some kinds of synthetic intermediates of halichlorine was investigated by using normal cell and some cancer cells. As a result, interestingly, the tricyclic core of halichlorine exhibited apoptosis-like activity.