Staurosporine-Derivatives

In contrast, UCN-01, a staurosporine derivative, acts as a potent inhibitor of the Chkl kinase and efficiently abrogates the G2 checkpoint upon DNA damage. Die forced entry into mitosis in the presence of DNA damage results in a mitotic form of apoptosis. Several clinical trials are currently exploring a combined treatment with UCN-01 and various DNA damaging diugs. In the same vein, inhibitors of Chk2 are developed and tested in clinical trials. 

Figure 8.26 Staurosporine derivatives generated using a two-plasmid system .

Beltran PJ, Fan D, Fidler IJ, O Brian CA (1997) Chemosensitization of cancer cells by the staurosporine derivative CGP 41251 in association with decreased P-glycoprotein phosphorylation. Biochem Pharmacol 53 245-247... 

Caravatti G, Meyer T, Fredenhagen A, Trinks U, Mett H, Fabbro D (1994) Inhibitory activity and selectivity of staurosporine derivatives towards protein kinase C. Bioorg Med Chem Lett 4 399-404... 

Schupp, P. Eder, C. Prdcsch, P. Wray, V. Schneider, B. Herderich, M. Paul, V. (1999) Staurosporine derivatives from the ascidian Eudistoma toealensis and its predatory flatworm Pseudoceros sp. J. Nat. Prod., 62,959-62. 

The isomeric pyranoindol-2-ones have also been used as relatively stable examples of indole quinodimethanes and offer a similar synthesis of carbazoles <90CC1667,90JCS(Pl)673,92JOC2105). An intramolecular version of this cycloaddition has been adapted to the synthesis of staurosporine derivatives and illustrates the synthetic process (Scheme 94). 

Schupp P, Proksch P, Wray V. Further new staurosporine derivatives fnan the ascidian Eudistoma toealensis and its predatory flatworm Pseudocerous sp. J Nat Prod 2002 65(3) 295-8. 

Schupp, P., Steube, K., Meyer, C., Proksch, P., (2001). Anti-proliferative effects of new staurosporine derivatives isolated from a marine ascidian and its predatory flatworm. Cancer Lett. 174, 165-172. 

Wakusawa S, Inoko K, Miyamoto K, Kajita S, Elasegawa K, Koyama M. Staurosporine derivatives reverse multidrug resistance without correlation with their protein kinase inhibitory activities. J. Antibiotics 1993 46 353-355. 

CGP 41251 is a staurosporine derivative with a high selectivity for protein kinase C entered recently in phase 1 clinical trial as an anticancer drug (Akiyama et al. 1999). Treatment of rat papillary muscle by this drug at 3 p,M reduced decreasing of contractility by simulated hypoxia and reperfusion (Kocic et al. 2001). 

Staurosporine Derivatives and Other Metabolites from Platyhelminthes... 

Table 5.1 ATP Dependent kinase IC50 values for staurosporine derivatives selectively inhibiting PKC isoforms.

Figure 3. NGF induced trk (A) and staurosporine induced gp " tyrosine phosphorylation in PC 12 cells. (A) PC 12 cultures were treated for 5, 15, 30 or 60 minutes with either NGF (50 ng/ml) or staurosporine (50 nM), lysed, immunoprecipitated with a pan-anti trk antibody, electrophoresed on SDS-PAGE, western blotted with a monoclonal anti P-Tyr antibody and developed with the ECL-Amersham reagent. TRK and IgG arrows indicate the position of NGF receptor and IgG used for immunoprecipitation. (B) Phosphotyrosine blotts of PC 12 cultures treated for 6 hours with either staurosporine (50 nM St.), K252a (200 nM), K252b (200 nM), a bisindolemaleimide-staurosporine derivative (100 nM GF, 109203X), KT5720 (500 nM) and control, DMSO 0.1% treated cultures. Numbers and arrows - the position of molecular weight markers.

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