Staurosporine

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Staurosporine
Staurosporine.svg
Staurosporine molecule ball.png
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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.109.946 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C28H26N4O3
Molar mass 466.541 g·mol−1
3D model (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 Yes check.svgY
  • Key:HKSZLNNOFSGOKW-FYTWVXJKSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Staurosporine (antibiotic AM-2282 or STS) is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus . [1] It was the first of over 50 alkaloids 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. [2]

Contents

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 inhibition of protein kinases 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. [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 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. [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

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 Structure of aIndolo(2,3-a)pyrrole(3,4-c)carbazol.svg
Structure of an Indolo[2,3-a]pyrrole[3,4-c]carbazol

Synthesis of Staurosporine.png

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.png

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 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 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]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Form of programmed cell death

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">GSK-3</span> Class of enzymes

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen synthase (GS), GSK-3 has since been identified as a protein kinase for over 100 different proteins in a variety of different pathways. In mammals, including humans, GSK-3 exists in two isozymes encoded by two homologous genes GSK-3α (GSK3A) and GSK-3β (GSK3B). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, addiction and bipolar disorder.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Chelerythrine</span> Chemical compound

Chelerythrine is a benzophenanthridine alkaloid present in the plant Chelidonium majus. It is a potent, selective, and cell-permeable protein kinase C inhibitor in vitro. And an efficacious antagonist of G-protein-coupled CB1 receptors. This molecule also exhibits anticancer qualities and it has served as a base for many potential novel drugs against cancer. Structurally, this molecule has two distinct conformations, one being a positively charged iminium form, and the other being an uncharged form, a pseudo-base.

<span class="mw-page-title-main">Seliciclib</span> Chemical compound

Seliciclib is an experimental drug candidate in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells. Seliciclib is being developed by Cyclacel. This is a phase II, dose ranging, multicenter, randomized, double-blind, placebo-controlled study.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

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<span class="mw-page-title-main">FADD</span> Human protein and coding gene

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<span class="mw-page-title-main">Rebeccamycin</span> Chemical compound

Rebeccamycin (NSC 655649) is a weak topoisomerase I inhibitor isolated from Nocardia bacteria. It is structurally similar to staurosporine, but does not show any inhibitory activity against protein kinases. It shows significant antitumor properties in vitro (IC50=480nM against mouse B16 melanoma cells and IC50=500nM against P388 leukemia cells). It is an antineoplastic antibiotic and an intercalating agent.

<span class="mw-page-title-main">PAK2</span> Mammalian protein found in Homo sapiens

Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.

<span class="mw-page-title-main">DNA damage-inducible transcript 3</span> Human protein and coding gene

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

<span class="mw-page-title-main">PIM2 (gene)</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Indolocarbazole</span> Class of chemical compounds

Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer as well as antimicrobial 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 throughout the world. Due to the extensive number of structures available, this review will focus on the more important groups here while covering their occurrence, biological activity, biosynthesis, and laboratory synthesis.

<span class="mw-page-title-main">BIM-1</span> Biological protein kinase C inhibitor

BIM-1 and the related compounds BIM-2, BIM-3, and BIM-8 are bisindolylmaleimide-based protein kinase C (PKC) inhibitors. These inhibitors also inhibit PDK1 explaining the higher inhibitory potential of LY33331 compared to the other BIM compounds a bisindolylmaleimide inhibitor toward PDK1.

<span class="mw-page-title-main">Midostaurin</span> Chemical compound

Midostaurin, sold under the brand name Rydapt by Novartis, is a multi-targeted protein kinase inhibitor that has been investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.

<span class="mw-page-title-main">Stauprimide</span> Chemical compound

Stauprimide 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. More recently, stauprimide has been shown to increase the efficiency of the directed differentiation of mouse and human embryonic stem cells in synergy with defined extracellular signaling cues. Stauprimide interacts with NME2 (PUF) transcription factor to down-regulate c-Myc expression, leading to differentiation of stem cells.

<span class="mw-page-title-main">Dinaciclib</span> Chemical compound

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<span class="mw-page-title-main">Cytotrienin A</span> Chemical compound

Cytotrienin A is a secondary metabolite isolated from Streptomyces sp. RK95-74 isolated from soil in Japan in 1997. Cyt A is an ansamycin. Cytotrienin A induces apoptosis on HL-60 cells, as well as inhibiting translation in eukaryotes by inhibiting eukaryotic elongation factor 1A (eEF1A), which can act as an oncogene. These functions lead to the potential of the microbial metabolite acting as an anticancer agent, specifically for blood cancers, as it has proved to be more effective with leukemic cell lines. Cyt A is thought to induce apoptosis by activating c-Jun N-terminal Kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and p36 myelin basic protein (MBP) kinase.

<span class="mw-page-title-main">6-Formylindolo(3,2-b)carbazole</span> Chemical compound

6-Formylindolo[3,2-b]carbazole (FICZ) is a chemical compound with the molecular formula C19H12N2O. It is a nitrogen heterocycle, having an extremely high affinity (Kd = 7 x 10−11M) for binding to the aryl hydrocarbon receptor (AHR).

Tautomycetin is a natural product first isolated from Streptomyces griseochromogenes, a bacterium found in the soil of the Zhejiang Province, China. It was also later found in Penicillium urticae. It is a linear polyketide very similar in structure to tautomycin, both of which contain a unique dialkylmaleic anhydride moiety, which is essential for their pharmacological activity. Tautomycetin is a selective inhibitor of protein phosphatase 1.

References

  1. ↑ 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 . PMID   863788.
  2. ↑ 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.
  3. ↑ 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. PMID   2672462.
  4. ↑ 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. PMID   18183025. S2CID   205273598.
  5. ↑ 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. PMC   2737611 . PMID   19519740.
  6. ↑ 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. PMID   10987998.
  7. ↑ 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. PMID   1728418.
  8. 1 2 3 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 Archived 2014-09-01 at the Wayback Machine product page, Fermentek
  10. ↑ 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. PMID   18508951. 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. ↑ 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 . PMC   3808212 . PMID   24174874.
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