Staurosporines, Cytotoxic Indolocabazole Alkaloids from the Marine Streptomyces sp.

Abstract

Staurosporine and its derivatives have aroused considerable interest as they were shown to have strong inhibitory activity against protein kinase C. Staurosporine also inhibits several other kinases such as protein kinases A and G, myosin light-chain kinase, and tyrosine kinases. The search for new staurosporine derivatives was further intensified after the discovery that staurosporine inhibits platelet aggregation and smooth muscle contraction and blocks certain phases of the cell-growth cycle. The most promising activity is the reversal of multidrug resistance by some derivatives. The potential of staurosporines as anticancer agents is clearly supported by the example of 7-hydroxystaurosporine (UNC-01), which is in clinical phase 1 trials at the NCI. As part of our continuing program to develop the biomedical potential of marine microorganisms, we have focused considerable attention on the marine actinomycetes. From a marine-derived actinomycete, we isolated two indolocarbazole alkaloids, staurosporines. We present here the discovery of staurosporines from marine Streptomyces sp. The isolation, structure determination, and cytotoxicity of staurosponies from marine Streptomyces will be presented. The isolation of staurosporines from a marine actinomycete supports the hypothesis that associated marine microorganisms are the real producers of staurosporines in the ascidian Eudistoma toealensis.