Search for new tyrosine-kinase inhibitors from marine organisms

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In this research project, we investigated on search for new tyrosine-kinase inhibitors from extracts of various marine invertebrates and microorganisms.From a sponge of Spongiidae family collected at Motobu-peninsula, Okinawa island, four new sesquiterpene quinones, nakijiquinones A-D,were isolated. These natural products as well as their synthetic analogs having one or two L-or D-amino acids exhibited inhibitory activity against c-erbB-2 kinase, while they were almost inactive against EGF receptor kinase and protein kinase C.Another sponge Psammaplysilla purea contained nine new bromotyrosine alkaloids, prealidins J-R,among which, purealidins J,K,P,and Q possessing spirocyclohexa-dienyl oxazole rings inhibited activity of EGF receptor kinase. From a marine bacterium Flavobacterium sp. isolated from a bivalve of Ishikari-bay, two new sulfonated ceramides, flavocristamides A and B,were isolated and they showed inhibitory activity against DNA polymerase alpha. We also found that other sponge metabolites such as bromopyrrole alkaloids and cyclic peptides had inhibition activity of tyrosine kinase. The tyrosine kinase inhibition activity of these marine natural products proved to be not so strong as known inhibitors (e. g., herbimycin) . More powerful and specific tyrosine kinase inhibitors may be found through further studies of structure-activity relationships on the new compounds obtained in this study.