K-252b, c and d, potent inhibitors of protein kinase C from microbial origin.

Abstract

Nocardiopsis sp. K-290 was found to produce novel metabolites, designated K-252b, c and d, which were structurally related to K-252a. These compounds were isolated from the culture broth and the physico-chemical and biochemical properties were examined. The compounds strongly inhibited protein kinase C. IC50 values (the concentrations causing 50 inhibition) for the effects of K-252b, c and d on the rat brain enzyme were 38.3, 214, and 337 nM, respectively. In a previous paper1), we reported that Nocardiopsis sp. K-252 produced a potent and new protein kinase C inhibitor, K-252a (1). In the present investigation, we have isolated three compounds, designated K-252b (2), c (3) and d (4), which are structurally related to K-252a, from the culture broth of Nocardiopsis sp. K-290. Similar to K-252a, these compounds strongly inhibited protein kinase C. This paper deals with fermentation, isolation and purification, and some biochemical properties of K-252b, c and d. Structural elucidation studies will be described in a succeeding paper2). Materials and Methods Microorganisms Nocardiopsis sp. K-290, isolated from a soil of Tama-shi, Tokyo, Japan, was employed in the present studies. Taxonomy of the strain will be described in a separate paper.

Selective kinase inhibitors as tools for neuroscience research

“…Around the same time other microbial metabolites e the K252 compounds e were found to have similar activities Nakanishi et al, 1986), and to have some limited selectivity between PKC and PKA (Kase et al, 1987). This spawned a class of molecules known as bisindolylmaleimides (Davis et al, 1992;Toullec et al, 1991) (Table 2) that have been widely used (Yaguchi et al, 2010;P.…”

Secondary metabolites of slime molds (myxomycetes)

“…14) and (Z)-methyl-2-hydroxy-3-(1H-indol-3-yl)acrylate (57) were isolated from L. epidendrum (Frö de et al, 1994). K-252 was previously found in a Nocardiopsis strain (Nakanishi et al, 1986). The red pigments arcyroxepins A (58) and B (59) were produced by A. denudata (Steglich, 1989).…”

Glycosylated Natural Products

“…The first class, exemplified by staurosporine, produced by Streptomyces staurosporeus (Scheme 25.8, 33), and K252a, possess an indolocarbazole subunit in which the indole nitrogens are bridged by glycosyl linkages and potent protein kinase C inhibitors [78][79][80]. The second group, exemplified by rebeccamycin from Saccharothrix aerocolonigenes (Scheme 25.8, 34), typically carry a single bglycoside critical to their interaction with DNA topoisomerase [81][82][83][84].…”