Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Staurosporine: Difference between pages

{{Short description|Chemical compound}}

| verifiedrevid = 470470622

| IUPAC_name = (''9S,10R,11R,13R'')-2,3,10,11,12,13-Hexahydro-<br/>10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-<br/>1''H'',9''H''-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]<br/>benzodiazonin-1-one

| width = 180px

| image2 = Staurosporine molecule ball.png

| alt2 = Ball-and-stick model of the staurosporine molecule

| width2 = 220

| routes_of_administration =

| excretion =

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = H88EPA0A3N

| IUPHAR_ligand = 346

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 162

| PDB_ligand = STU

<!--Chemical data-->

| C=28 | H=26 | N=4 | O=3

'''Staurosporine''' (antibiotic AM-2282 or STS) is a [[natural product]] originally isolated in 1977 from the bacterium ''[[Streptomyces staurosporeus]]''.<ref name="omura">{{cite journal | vauthors = Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchya H, Takahashi Y, Masuma R | display-authors = 6 | title = A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization | journal = The Journal of Antibiotics | volume = 30 | issue = 4 | pages = 275–282 | date = April 1977 | pmid = 863788 | doi = 10.7164/antibiotics.30.275 | doi-access = free }}</ref>

It was the first of over 50 [[alkaloid]]s that were discovered to share this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by [[X-ray crystalography]] in 1994.<ref name=funato>{{cite journal |vauthors=Funato N, Takayanagi H, Konda Y, Toda Y, Harigaya Y, Omura S |title= Absolute configuration of staurosporine by X-ray analysis |journal= Tetrahedron Lett. |volume= 35 |issue= 8 |pages= 1251–1254 |year= 1994 |doi= 10.1016/0040-4039(94)88036-0}}</ref>

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive.<ref name="pmid2672462">{{cite journal | vauthors = Rüegg UT, Burgess GM | title = Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases | journal = Trends in Pharmacological Sciences | volume = 10 | issue = 6 | pages = 218–20 | date = June 1989 | pmid = 2672462 | doi = 10.1016/0165-6147(89)90263-0 }}</ref>

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 [[enzyme inhibition|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.<ref name="ambit">{{cite journal | vauthors = Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP | display-authors = 6 | title = A quantitative analysis of kinase inhibitor selectivity | journal = Nature Biotechnology | volume = 26 | issue = 1 | pages = 127–132 | date = January 2008 | pmid = 18183025 | doi = 10.1038/nbt1358 | s2cid = 205273598 }}</ref> Structural analysis of kinase pockets demonstrated that main chain atoms which are conserved in their relative positions to staurosporine contributes to staurosporine promiscuity.<ref name="tanramluk">{{cite journal | vauthors = Tanramluk D, Schreyer A, Pitt WR, Blundell TL | title = On the origins of enzyme inhibitor selectivity and promiscuity: a case study of protein kinase binding to staurosporine | journal = Chemical Biology & Drug Design | volume = 74 | issue = 1 | pages = 16–24 | date = July 2009 | pmid = 19519740 | pmc = 2737611 | doi = 10.1111/j.1747-0285.2009.00832.x }}</ref> 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]].<ref name="Chae">{{cite journal | vauthors = Chae HJ, Kang JS, Byun JO, Han KS, Kim DU, Oh SM, Kim HM, Chae SW, Kim HR | display-authors = 6 | title = Molecular mechanism of staurosporine-induced apoptosis in osteoblasts | journal = Pharmacological Research | volume = 42 | issue = 4 | pages = 373–381 | date = October 2000 | pmid = 10987998 | doi = 10.1006/phrs.2000.0700 }}</ref> 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.<ref>{{cite journal | vauthors = Bruno S, Ardelt B, Skierski JS, Traganos F, Darzynkiewicz Z | title = Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes | journal = Cancer Research | volume = 52 | issue = 2 | pages = 470–473 | date = January 1992 | pmid = 1728418 }}</ref>

==Chemistry family==

{{main|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.<ref name="urldspace.mit.edu">{{cite web| url =http://dspace.mit.edu/bitstream/handle/1721.1/45151/314357162.pdf?sequence=1| title =Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes| vauthors = Ryan KS| year =2008| work =Ph.D. Thesis| publisher =Massachusetts Institute of Technology| archive-url =https://web.archive.org/web/20120314013836/http://dspace.mit.edu/bitstream/handle/1721.1/45151/314357162.pdf?sequence=1| archive-date =2012-03-14| url-status =dead}}</ref>

Staurosporine is the precursor of the novel [[protein kinase inhibitor]] [[midostaurin]] (PKC412).<ref>[http://www.fermentek.co.il/pkc412.htm Midostaurin] {{Webarchive|url=https://web.archive.org/web/20140901063956/http://www.fermentek.co.il/pkc412.htm |date=2014-09-01 }} product page, [[Fermentek]]</ref><ref>{{cite journal | vauthors = Wang Y, Yin OQ, Graf P, Kisicki JC, Schran H | title = Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus | journal = Journal of Clinical Pharmacology | volume = 48 | issue = 6 | pages = 763–775 | date = June 2008 | pmid = 18508951 | doi = 10.1177/0091270008318006 | s2cid = 26657407 }}</ref> 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.

[[File:Structure of aIndolo(2,3-a)pyrrole(3,4-c)carbazol.svg|thumb|300px|Structure of an Indolo[2,3-a]pyrrole[3,4-c]carbazol]]

[[File:Synthesis of Staurosporine.png|500px|Synthesis of Staurosporine]]

== Biosynthesis ==

The biosynthesis of staurosporine starts with the amino acid [[L-tryptophan]] in its [[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|cytochrome P₄₅₀]] enzyme to form an aromatic ring system occurs.<ref name="urldspace.mit.edu"/>

[[File:Staurosporine 2.png|500px|Staurosporine 2]]

This is followed by a [[nucleophile|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.<ref name="urldspace.mit.edu"/>

== Research in preclinical use ==

When encapsulated in [[liposome]] [[nanoparticle]], staurosporine is shown to suppress tumors ''in vivo'' in a mouse model without the toxic side effects which have prohibited its use as an anti-cancer drug with high apoptotic activity. Researchers in [[UC San Diego Health System|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 in the life sciences|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.<ref>{{cite web|url= http://health.ucsd.edu/news/releases/Pages/2013-10-21-potent-anti-cancer-drug-delivered-in-liposomes.aspx|title=Study Identifies Safe Delivery System for Tricky Yet Highly Potent Anti-Cancer Compounds|author=News Release|publisher=UC San Diego Health System|date=21 October 2013|access-date=27 October 2013}}</ref><ref>{{cite journal | vauthors = Mukthavaram R, Jiang P, Saklecha R, Simberg D, Bharati IS, Nomura N, Chao Y, Pastorino S, Pingle SC, Fogal V, Wrasidlo W, Makale M, Kesari S | display-authors = 6 | title = High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile | journal = International Journal of Nanomedicine | volume = 8 | issue = 1 | pages = 3991–4006 | year = 2013 | pmid = 24174874 | pmc = 3808212 | doi = 10.2147/IJN.S51949 | doi-access = free }}</ref>

== List of compounds closely related to Staurosporine ==

* [[K252a]]

* [[Stauprimide]]

* [[Midostaurin]]

== References ==

{{reflist}}

[[Category:Bacterial alkaloids]]

[[Category:Antibiotics]]

[[Category:Gamma-lactams]]

[[Category:Protein kinase inhibitors]]

[[Category:Indolocarbazoles]]