Search for new tyrosine-kinase inhibitors from marine organisms

本课题主要从各种海洋无脊椎动物和微生物的提取物中寻找新的酪氨酸激酶抑制剂。从冲绳本本半岛采集的海绵科海绵中分离到4个新的倍半萜醌类化合物，分别为七次醌a - d。这些天然产物及其合成类似物具有1个或2个l -或d -氨基酸，对c-erbB-2激酶具有抑制活性，而对EGF受体激酶和蛋白激酶c几乎无活性。另外，海绵Psammaplysilla purea含有9种新的溴酪氨酸生物碱，预醛素J- r，其中含有螺环己二烯基oxazole环的预醛素J、K、P和Q抑制EGF受体激酶的活性。从石卡里湾双壳类海洋细菌黄杆菌中分离到两种新的磺化神经酰胺黄酮胺a和黄酮胺B，它们具有抑制DNA聚合酶α的活性。我们还发现其他海绵代谢物如溴吡咯生物碱和环肽对酪氨酸激酶有抑制作用。这些海洋天然产物的酪氨酸激酶抑制活性被证明不如已知的抑制剂（如herbyycin）那么强。通过进一步研究本研究获得的新化合物的结构-活性关系，可能会发现更强效和特异性的酪氨酸激酶抑制剂。

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.