Inhibitors staurosporine

Figure 6.15. Structures of some protein kinase C inhibitors. Staurosporine is a potent inhibitor of protein kinase C, but is not selective. Some derivatives of protein kinase C, such as Ro31-8220 and Ro31-8425, retain a potency similar to that of the parent molecule in protein kinase C inhibition, but are much more specific.

S6, and SlOb) and two 20S a-subunits (C8 and C9) are known to be phosphoryl-ated. Phosphorylation appears to be particularly important for 26S proteasome assembly and stability. The kinase inhibitor staurosporine reduces 26S proteasome levels in mouse lymphoma cells [135] and interferon y results in reduced phosphorylation of 20S proteasome a-subunits and decreased 26S proteasome levels [141]. 

Sandiez-Margalet V, Lucas M, Solano F, Goberna R (1993) Sensitivity of insulin-secreting RIN m5F cells to undergoing apoptosis by the protein kinase C inhibitor staurosporine. Exp Cell Res 209 160-163... 

Quercetin also inhibited rat aortic contractions induced by noradrenaline, 5-hydroxytryptamine, and caffeine in Ca2+ -free media [110]. PMA enhanced this transient contraction elicited by noradrenaline, an effect that was abolished by quercetin. Furthermore, quercetin or the PKC inhibitor staurosporine, had no effect on 45Ca2+ efflux under resting conditions or when stimulated by noradrenaline. So, the inhibitory effects of quercetin on phasic contractile response induced by receptor agonists in... 

The potent protein kinase inhibitor staurosporine (121) was first isolated in 1977 from the actinomycete strain AM-2282 [133], which was later reclassified as Lentzea albida [134]. Staurosporine (121) has received immense attention as a potential chemotherapeutic, possessing nanomolar inhibitory activity against protein kinase C (PKC) [135]. Its inhibitory activity against multiple protein kinases in cells has prompted an investigation of related molecules with less potent, but more PKC-specific, activity [12, 136]. A related molecule, UCN-01 or 7-hydroxy-staurosporine (122), differing from staurosporine (121) only in the presence of a... 

Herrero et al. (1998) then found that, while the stimulatory effect of 3,5-DHPG on the 4-AP (50 pM)-evoked glutamate release was PKC-dependent, its inhibitory effect on the 4-AP(l mM)-evoked release was not altered by the PKC inhibitor staurosporine. PKC activity was, however, involved in the switch from release facilitation to release inhibition. To show this, nerve terminals were pre-exposed to 3,5-DHPG for 1 min to induce the switch, washed and treated with staurosporine. Under these conditions, the inhibitory effect of 3,5-DHPG on the 4-AP(lmM)-evoked glutamate exocytosis remained unaltered. Conversely, in experiments in which the exposure to 3,5-DHPG occurred after a prior inhibition of PKC with staurosporine, the second stimulation with 3,5-DHPG failed to induce release inhibition. 

Chart 9 The kinase inhibitor staurosporine and the ruthenium complex DW1/2... 

Fig. 2 Schematic representation of the hydrogen bonding contacts with the hinge region of the highly conserved ATP-binding site of protein kinases the natural substrate ATP (left) the organic inhibitor staurosporine (center) a metallo-pyridocarbazole scaffold (right)...

Synthetic approaches to the benzodipyrrole units in the antitumour agent CC-1065 (155) and the protein kinase C inhibitor staurosporine (170) are discussed briefly in Section 7.21.12. 

Protein kinase C inhibitor, staurosporine Enhancement of nifedipine (L-type calcium channel blocker) induced afferent arteriolar dilation in spontaneously hypertensive rats. [260]... 

This effect was greatly reduced by the PKC inhibitor staurosporine, which means that PKC plays a major role in daphnoretin-induced respiratory burst. Daphnoretin, like TPA, increased the membrane associated PKC activity in neutrophil suspension. It is possible that daphnoretin, like TPA, may bypass the membrane receptor and act as a PKC activator. Daphnoretin reduced the [ HjPDBu binding to PKC in a... 

Tischler, AS. Ruzicka, A. Dobner, P.R. (1991). A pa-otein kinase inhibitor, staurosporine, mimics nerve growth factor induction of neurotensin/neuromedin N gene expression. J Biol Chem, Vol. 266(2), pp. 1141-6. 

The protein kinase C inhibitor, staurosporine (100 nM) significantly inhibited the production of IL-8 by a human monocytic cell line, MonoMac6 stimulated by LPS, and so did the tyrosine kinase inhibitor, genistein (25 pM) (Fujishima et al. 1997). 

Glycal related dienes like 19, prepared by base treatment of the corresponding 6-<9-mesyl glycals have been described as substrates for epoxidation with dimethyldioxirane, mid are usefiil precursors for making the protein kinase C inhibitor, staurosporine. ... 

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