SEARCH FOR METABOLITES INFLUENCING CELLAR FUNCTION FROM AQUATIC INVERTEBRATES AND ANLYSIS OF THEIR MODES OF ACTION.

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A number of marine invertebrates including sponges, soft corals, and tunicates collected from various Japanese coasts has been tested for cytotoxicity against P388 leukemia cells, morphological changes-inducing activity in rat neuroblast 3Y1, inhititory activity against serine proteases, cystein proteases, metalloproteinases, and glycosidases. Isolation and structure elucidation of active constituents from promising specimens resulted in discovery of 71 new compounds, among which calmodulin-inhibiting alkaloids were included. Biological activity studies of new calyculin derivatives and those derived chemically from calyculin A led to important insights into the interaction of calyculins with protein phosphatases.Detailed analyses of modes of action of selective compounds obtained led to several inportant findings. Mycalolides/kabiramides bind to a different site of actin from those of cytochalasin D and latrunculin A.Bistheonellide A bind to G-actin in a molar ration of 1 : 2 to inhibit actin polymerization. Stellettamide A and related alkaloids induce contraction of smooth muscles which was found to be due to inhibition of phosphorylation of myosin light chain by inhibiting calmodulin. It was also found that discodermin A forms pores in biomembranes and that theonellamides A and F interact with dehydrogenases.In search for metabolites affecting development of echinoderm embryos, several active substances were isolated from sponges including ancorinoside A and rhopaloic acids. Jaspisin was found to inhibit selectively a hatching enzyme of sea urchin, a matrix endopeptidase. Finally, a simple system to detect inhibitors of protein phosphatases such as okadaic acid and calyculin A by using antibodies which differentiate specific phosphorylated amino acids in ANO39, an endoplasmic reticulum protein of sea urchin eggs.