Staurosporine
Encyclopedia
Staurosporine is a natural product
originally isolated in 1977 from the bacterium Streptomyces
staurosporeus.
It was the first of over 50 alkaloid
s to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.
Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive.
The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment.
The main biological activity of staurosporine is the inhibition of protein kinase
s through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase. Staurosporine is a prototypical ATP-competitive kinase inhibitor in that it binds to many kinases with high affinity, though with little selectivity.
This lack of specificity has precluded its clinical use, but has made it a valuable research tool. In research, staurosporine is used to induce apoptosis
. The mechanism of how it mediates this is not well understood. It has been found that one way in which staurosporine induces apoptosis is by activating caspase-3.
Staurosporine is the precursor of the novel protein kinase inhibitor
midostaurin
(PKC412). Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.
s belong to the alkaloid
sub-class of bisindoles. Of these carbazole
s the Indolo(2,3-a)carbazoles are the most frequently isolated; the most common subgroup of the Indolo(2,3-a)carbazoles are the Indolo(2,3-a)pyrrole(3,4-c)carbazoles which can be divided into two major classes - halogenated (chlorinated) with a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond and the second class consists of both indole nitrogen glycosilated, non-halogenated, and a fully reduced C-7 carbon. Staurosporine is part of the second non-halogenated class.
The biosynthesis of staurosporine starts with the amino acid L-tryptophan in it zwitterion
ic form. Tryptophan is converted to an imine
by enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin
. An aryl aryl coupling thought to be catalyzed by a cytochrome P450 enzyme to form an aromatic ring system occurs.
This is followed by a nucleophilic attack
between the indole nitrogens resulting in cyclization and then decarboxylation
assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose
is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4'amine by StaMA and N-methylation of the 3'-hydroxy by StaMB leads to the formation of staurosporine.
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
originally isolated in 1977 from the bacterium Streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
staurosporeus.
It was the first of over 50 alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.
Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive.
The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment.
The main biological activity of staurosporine is the inhibition of protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase. Staurosporine is a prototypical ATP-competitive kinase inhibitor in that it binds to many kinases with high affinity, though with little selectivity.
This lack of specificity has precluded its clinical use, but has made it a valuable research tool. In research, staurosporine is used to induce apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. The mechanism of how it mediates this is not well understood. It has been found that one way in which staurosporine induces apoptosis is by activating caspase-3.
Staurosporine is the precursor of the novel protein kinase inhibitor
Protein kinase inhibitor
A protein kinase inhibitor is a type of enzyme inhibitor that specifically blocks the action of one or more protein kinases. Hence, they can be subdivided or characterised by the amino acids whose phosphorylation is inhibited:...
midostaurin
Midostaurin
Midostaurin is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia and myelodysplastic syndrome...
(PKC412). Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.
Biosynthesis
IndolocarbazoleIndolocarbazole
Indolocarbazoles are a class of compounds that are under current study due to their potential as anti-cancer drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range of structures and derivatives have been found or developed...
s belong to the alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
sub-class of bisindoles. Of these carbazole
Carbazole
Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six-membered benzene ring fused on either side of a five-membered nitrogen-containing ring...
s the Indolo(2,3-a)carbazoles are the most frequently isolated; the most common subgroup of the Indolo(2,3-a)carbazoles are the Indolo(2,3-a)pyrrole(3,4-c)carbazoles which can be divided into two major classes - halogenated (chlorinated) with a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond and the second class consists of both indole nitrogen glycosilated, non-halogenated, and a fully reduced C-7 carbon. Staurosporine is part of the second non-halogenated class.
The biosynthesis of staurosporine starts with the amino acid L-tryptophan in it zwitterion
Zwitterion
In chemistry, a zwitterion is a neutral molecule with a positive and a negative electrical charge at different locations within that molecule. Zwitterions are sometimes also called inner salts.-Examples:...
ic form. Tryptophan is converted to an imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
by enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin
Rebeccamycin
Rebeccamycin is a weak topoisomerase I inhibitor isolated from Streptomyces sp. structurally similar to staurosporine. Does not show any inhibitory activity against protein kinases. Shows significant antitumor properties in vitro ....
. An aryl aryl coupling thought to be catalyzed by a cytochrome P450 enzyme to form an aromatic ring system occurs.
This is followed by a nucleophilic attack
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
between the indole nitrogens resulting in cyclization and then decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4'amine by StaMA and N-methylation of the 3'-hydroxy by StaMB leads to the formation of staurosporine.
List of compounds closely related to Staurosporine
- K252aK252aK252a is an alkaloid isolated from Nocardiopisis sp. soil fungi. This staurosporine analog is a highly potent cell permeable inhibitor of CaM kinase and phosphorylase kinase...
- StauprimideStauprimideStauprimide is a semi-synthetic analog of the staurosporine family of indolocarbazoles. Stauprimide was first published in 1994 as part of an extensive structure-activity investigation to improve the selective inhibition of protein kinase C as a potential antitumor agent...
- MidostaurinMidostaurinMidostaurin is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia and myelodysplastic syndrome...
- UCN-01