Staurosporeus

S. staurosporeus Anaya Actinomadura madurae A. melliaura Arcyria denudata Aspergillus flavus A. tubingensis Nocardia aerocoligenes Nocardiopsis dassonvillei Nocardiopsis sp. 

In 1990, researchers at Bristol-Myers Squibb reported the isolation of Bmy-41950 (322) from S. staurosporeus strain R10069 (ATCC 55006). This isolate showed in vitro activity against human colon cancer cells (HCT-116) (307). Two years later, Isono et al. reported the isolation of the same natural product from a different Streptomyces sp., S. platensis subsp. malvinus RK-1409 and named it RK-1409 (7-oxostaurosporine) (322) (308,309). In nature, this isolate was obtained in its optically active form [ Id + 38.3 (c 0.06, CHCI3) (309). The PKC inhibitor RK-1409 (7-oxostaurosporine) inhibited the morphological change of a human erythroleukemia cell line, K-562, induced by phorbol 12,13-dibutyrate (PDBu), and also showed a weak antimicrobial activity against Chlorella vulgaris and Pyricularia oryzae (308). 

Isolated in 1977 from the bacterium Streptomyces staurosporeus, staurosporine (3) is a natural product that inhibits most protein kinases at low nanomolar concentrations [23]. Through small-molecule/protein complex cocrystallization, it was shown that staurosporine binds tightly to the adenosine binding pocket ofthe catalytic subunit of the cAMP-dependent protein kinase. Chelerythrine (4) was identified as an inhibitor of Bcl-XL-Bak BH3 peptide binding vdth an IC50 of 1.5 p,M, and also displaced Bax from Bcl-XL [24]. Chelidonine (S) is another example of an alkaloid natural product that inhibits the taxol-mediated polymerization of tubulin in the micromolar range ( 24.0 p,M). 

The biosyntheses of STA and REB were studied by feeding radiolabeled precursors to Lentzea albida (formerly Streptomyces staurosporeus) [9-13] and Lechevalieria aero-colonigmes (formerly Saccharothix aerocolonigenes) [14,15], respectively. The results established that the indolocarbazole core was derived from two units of tryptophan (with the carbon skeleton incorporated intact), while the sugar moiety was derived from glucose and methionine (for methylations). 

Staurosporine (36), an indole carbazol alkaloid isolated from Streptomyces staurosporeus was considered the most potent protein kinase inhibitor until the discovery of balanol. Staurosporine is not a selective inhibitor because it also inhibits PKA, PKG and tyrosine kinases at similar concentrations [1], This compound has significant cytotoxic and antiproliferative effects in vitro and several of its related analogues show antitumour activity in animal models. In addition, staurosporine and derivatives have been used to explore the role of PKC in cell functions. For instance, Jordan et al. [95] studied the ability of staurosporine and other PKC inhibitors to affect TNFa and interleukin-la (EL-la)-induced chemokine gene expression and protein production in synovial fibroblasts. In these circumstances, staurosporine enhanced IL-la-induced chemokine mRNA production. A possible explanation for this result is that the mechanisms of gene expression could be negatively regulated by different isoforms of PKC. [95]. Previously it had been observed that staurosporine... 

Staurosporine, a natural product isolated from Streptomyces staurosporeus, is a relatively broad, nonspecific protein kinase antagonist, originally isolated in an effort to define inhibitors of protein kinase C (PKC). 7-OH staurosporine (UCN-01) was defined as a more selective, but not specific, PKC antagonist. UCN-01 inhibits classic lipid and calcium-dependent PKCs a, ft, and y (IC50 = 4-30 nM), Ca2+-independent PKCs and less potently (IC 50 approximately 500 nM), and is without effect on the atypical PKCs, e.g., PKC f (97). 

Staurosporine, an indolo-2,3-carbazole alkaloid, was first isolated from Streptomyces staurosporeus [46] and subsequently from other... 

The first-generation of PKC inhibitors include staurosporine, a natural product originally isolated in 1977 from bacterium Streptomyces staurosporeus. Staurosporine was the first of over 50 alkaloids to be isolated with this type of bis-indole core structure. However, staurosporine inhibits PKC isoforms non-selectively, and this lack of specificity precludes its clinical use due to toxicity concerns. Nevertheless, staurosporine has become a valuable research tool to induce apoptosis. In addition, staurosporine serves as a versatile starting material for the synthesis of novel semisynthetic analogs. 

The same chromophore as is found in the arcyriaflavins occurs also in rebeccamycin (516) and in its dechloro derivative, two antitumour antibiotics isolated from Nocardia aerocoligenes 510). Also closely related to these compounds are staurosporin (517), an antibiotic from Streptomyces staurosporeus which exhibits pronounced antihypotensive activity 258), and other carbohydrate bridged bisindoles (575). Due to the small amounts of Arcyria metabolites available from the... 

Inhibitors of protein kinases bioddng the ceU cycie in phase Gi are common, but those that biock the cyde in phase G2 (a phase preparatory to mitosis) are much rarer. Among them are caffeine and staurosporine, which is of fungai origin (Streptomyces staurosporeus), but there are analogs in some ascidians (see below). For information on the cell cycle, see the list of websites at the end of this chapter. 

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