Chemical Studies toward Development of Nerve Cell Degeneration Repairing or Protecting Agent

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This research project has been performed toward development of nerve cell degeneration repairing and/or protecting agent from novel neurotrophic natural products. The following results have been obtained.(1) An unprecedented macrocyclic vibsane-type diterpene bearing an endo-peroxide in the molecule and novel limonoids were isolated as new neurotrophic active substances from the leaves of Viburnum awabuki and the roots of Melia azedarach Linn ver. Japonica, respectively.(2) The first synthesis of plagiochin A, a 16-membered bis(bibenzyl) which is one of the potent neurotrophic natural products has been accomplished by an intramolecular Pd(O)-catalyzed Still-Kelly reaction. Another neurotrophic sesquiterpenes dimers, mastigophorenes A and B have been obtained by oxidative phenol coupling of (+)-herebertendiol, which was already synthesized by applying an intramolecular Heck reaction to the construction of the quaternary carbon center linked to the benzene ring. The extremely simple syntheses of neurotrophic active substnaces, americanol A and isoamericanol A which were isolated from Phytolacca americana have been performed by HRP-catalyzed oxidative dimerization of caffeic acid.(3) Plant tissue culture has been applied to produce americanol A and isoamericanol A in the callus of Phytolacca americana, but their formation has not been so far realized. The callus successfully induced from the seeds of Belamcanda chinensis is now subjected to study on the condition of liquid culture. We will continue working on the production and biotransformation of neurotrophic active substances by using the plant tissue culture.(4) Apotosis system in the cell culture of fetal rat cerebral hemisphere has been modified, and thereby we will be able to screen natural products which inhibit the apotosis of the nerve cell induced by beta-amyloid protein.