Staurosporine
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| ECHA InfoCard | 100.109.946 |
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| Formula | C28H26N4O3 |
| Molar mass | 466.541g·mol−1 |
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Staurosporine(antibiotic AM-2282 or STS) is anatural productoriginally isolated in 1977 from the bacteriumStreptomyces staurosporeus.[1] It was the first of over 50alkaloidsthat were discovered to share this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated byX-ray crystalographyin 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
[edit]The main biological activity of staurosporine is theinhibitionofprotein kinasesthrough 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.[4]Structural analysis of kinase pockets demonstrated that main chain atoms which are conserved in their relative positions to staurosporine contributes to staurosporine promiscuity.[5]This lack of specificity has precluded its clinical use, but has made it a valuable research tool. In research, staurosporine is used to induceapoptosis.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 activatingcaspase-3.[6]At lower concentration, depending on the cell type, staurosporine induces specific cell cycle effects arresting cells either in G1or in G2phase of the cell cycle.[7]
Chemistry family
[edit]Staurosporine is anindolocarbazole.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 novelprotein kinase inhibitormidostaurin(PKC412).[9][10]Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis ofK252c(also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.
Biosynthesis
[edit]The biosynthesis of staurosporine starts with the amino acidL-tryptophanin itszwitterionicform. Tryptophan is converted to animineby 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 ofviolacein– a natural product formed from a branch point in this pathway that also diverges to formrebeccamycin.An aryl aryl coupling thought to be catalyzed by acytochrome P450enzyme to form an aromatic ring system occurs.[8]
This is followed by anucleophilic attackbetween the indole nitrogens resulting in cyclization and thendecarboxylationassisted by StaC exclusively forming staurosporine aglycone or K252c.Glucoseis 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
[edit]When encapsulated inliposomenanoparticle,staurosporine is shown to suppress tumorsin vivoin a mouse model without the toxic side effects which have prohibited its use as an anti-cancer drug with high apoptotic activity. Researchers inUC San Diego Moores Cancer Centerdevelop a platform technology of high drug-loading efficiency by manipulating the pH environment of the cells. When injected into the mouseglioblastomamodel, staurosporine is found to accumulate primarily in the tumor viafluorescenceconfirmation, 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
[edit]References
[edit]- ^Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchya H, et al. (April 1977)."A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization".The Journal of Antibiotics.30(4): 275–282.doi:10.7164/antibiotics.30.275.PMID863788.
- ^Funato N, Takayanagi H, Konda Y, Toda Y, Harigaya Y, Omura S (1994). "Absolute configuration of staurosporine by X-ray analysis".Tetrahedron Lett.35(8): 1251–1254.doi:10.1016/0040-4039(94)88036-0.
- ^Rüegg UT, Burgess GM (June 1989). "Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases".Trends in Pharmacological Sciences.10(6): 218–20.doi:10.1016/0165-6147(89)90263-0.PMID2672462.
- ^Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. (January 2008). "A quantitative analysis of kinase inhibitor selectivity".Nature Biotechnology.26(1): 127–132.doi:10.1038/nbt1358.PMID18183025.S2CID205273598.
- ^Tanramluk D, Schreyer A, Pitt WR, Blundell TL (July 2009)."On the origins of enzyme inhibitor selectivity and promiscuity: a case study of protein kinase binding to staurosporine".Chemical Biology & Drug Design.74(1): 16–24.doi:10.1111/j.1747-0285.2009.00832.x.PMC2737611.PMID19519740.
- ^Chae HJ, Kang JS, Byun JO, Han KS, Kim DU, Oh SM, et al. (October 2000). "Molecular mechanism of staurosporine-induced apoptosis in osteoblasts".Pharmacological Research.42(4): 373–381.doi:10.1006/phrs.2000.0700.PMID10987998.
- ^Bruno S, Ardelt B, Skierski JS, Traganos F, Darzynkiewicz Z (January 1992). "Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes".Cancer Research.52(2): 470–473.PMID1728418.
- ^abcRyan KS (2008)."Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes"(PDF).Ph.D. Thesis.Massachusetts Institute of Technology. Archived fromthe original(PDF)on 2012-03-14.
- ^MidostaurinArchived2014-09-01 at theWayback Machineproduct page,Fermentek
- ^Wang Y, Yin OQ, Graf P, Kisicki JC, Schran H (June 2008). "Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus".Journal of Clinical Pharmacology.48(6): 763–775.doi:10.1177/0091270008318006.PMID18508951.S2CID26657407.
- ^News Release (21 October 2013)."Study Identifies Safe Delivery System for Tricky Yet Highly Potent Anti-Cancer Compounds".UC San Diego Health System.Retrieved27 October2013.
- ^Mukthavaram R, Jiang P, Saklecha R, Simberg D, Bharati IS, Nomura N, et al. (2013)."High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile".International Journal of Nanomedicine.8(1): 3991–4006.doi:10.2147/IJN.S51949.PMC3808212.PMID24174874.