Staurosporine

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Staurosporine
Ball-and-stick model of the staurosporine molecule
Clinical data
ATC code
  • none
Identifiers
  • (9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-
    10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-
    1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]
    benzodiazonin-1-one
JSmol)
  • C[C@@]12[C@@H]([C@@H](C[C@@H](O1)n3c4ccccc4c5c3c6n2c7ccccc7c6c8c5C(=O)NC8)NC)OC
  • InChI=1S/C28H26N4O3/c1-28-26(34-3)17(29-2)12-20(35-28)31-18-10-6-4-8-14(18)22-23-16(13-30-27(23)33)21-15-9-5-7-11-19(15)32(28)25(21)24(22)31/h4-11,17,20,26,29H,12-13H2,1-3H3,(H,30,33)/t17-,20-,26-,28+/m1/s1 checkY
  • Key:HKSZLNNOFSGOKW-FYTWVXJKSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Staurosporine (antibiotic AM-2282 or STS) is a

Streptomyces staurosporeus.[1]
It was the first of over 50
X-ray crystalography in 1994.[2]

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive.[3] 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.

Biological activities

The main biological activity of staurosporine is the

caspase-3.[6] At lower concentration, depending on the cell type, staurosporine induces specific cell cycle effects arresting cells either in G1 or in G2 phase of the cell cycle.[7]

Chemistry family

Main article: Indolocarbazole

Staurosporine is an indolocarbazole. It belongs to the most frequently isolated group of indolocarbazoles: Indolo(2,3-a)carbazoles. Of these, Staurosporine falls within the most common subgroup, called Indolo(2,3-a)pyrrole(3,4-c)carbazoles. These fall into two classes - halogenated (chlorinated) and non-halogenated. Halogenated indolo(2,3-a)pyrrole(3,4-c)carbazoles have a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond, while non-halogenated indolo(2,3-a)pyrrole(3,4-c)carbazoles have both indole nitrogens glycosylated, and a fully reduced C-7 carbon. Staurosporine is in the non-halogenated class.[8]

Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin (PKC412).[9][10] 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.

Structure of an Indolo[2,3-a]pyrrole[3,4-c]carbazol

Synthesis of Staurosporine

Biosynthesis

The biosynthesis of staurosporine starts with the amino acid

L-tryptophan in its zwitterionic 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.[8]

Staurosporine 2

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.[8]

Research in preclinical use

When encapsulated in

UC San Diego Moores Cancer Center develop a platform technology of high drug-loading efficiency by manipulating the pH environment of the cells. When injected into the mouse glioblastoma model, staurosporine is found to accumulate primarily in the tumor via fluorescence confirmation, and the mice did not suffer weight loss compared to the control mice administered with the free compound, an indicator of reduced toxicity.[11][12]

List of compounds closely related to Staurosporine

References

  1. PMID 863788
    .
  2. doi:10.1016/0040-4039(94)88036-0
    .
  3. PMID 2672462
    .
  4. S2CID 205273598
    .
  5. PMID 19519740
    .
  6. PMID 10987998
    .
  7. PMID 1728418
    .
  8. ^ a b c Ryan KS (2008). "Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes" (PDF). Ph.D. Thesis. Massachusetts Institute of Technology. Archived from the original (PDF) on 2012-03-14.
  9. ^ Midostaurin product page, Fermentek
  10. S2CID 26657407
    .
  11. ^ News Release (21 October 2013). "Study Identifies Safe Delivery System for Tricky Yet Highly Potent Anti-Cancer Compounds". UC San Diego Health System. Retrieved 27 October 2013.
  12. PMID 24174874
    .
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