The staurosporine producing strain Streptomyces longisporoflavus produces metabolites related to K-252a. Proposal for biosynthetic intermediates of K-252a.

Yang Cai, Andreas Fredenhagen*, Paul HuGf and Heinrich H. Peter Core Drug Discovery Technologies, Pharmaceutical Research and t Research Services, Physics Department, CIBA-GEIGY Ltd., 4002 Basel, Switzerland (Received for publication April 1, 1996) Alkaloids of the indolocarbazole type bind to ATP-binding sites of various enzymes. Staurosporine isolated from Saccharothrix aerocolonigenes subsp. staurosporeusX) was found to be an inhibitor of protein kinase C (PKC) in the low nanomolar range2). Most other alkaloids of this type contain a six-membered sugar moiety like staurosporine3~6). A subgroup of these metabolites are K-252a (6)7) and K-252b8), which were isolated by Japanese researchers from two Nocardiopsis species strains as PKC inhibitors. In contrast to staurosporine these secondary metabolites have a fivememberedsugar moiety and a carboxylate function attached to this ring. Although a weaker inhibitor of PKCthan staurosporine, K-252b attracted considerable interest as it is able to potentiate neurotrophin-3 actions in vitro9). In previous publications we described several minor metabolites of Streptomyces longisporoflavus strain R-19 which were isolated as byproducts of a large scale staurosporine fermentation6' 1 0). In the present communication the structure elucidation, physicochemical data, and biological properties of further minor metabolites are described. Fermentation6) and isolation10) of the new compounds werereported earlier.