Aloisine A - CAS 496864-16-5
Catalog number: 496864-16-5
Category: Inhibitor
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Molecular Formula:
C16H17N3O
Molecular Weight:
267.33
COA:
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Targets:
CDK
Description:
Aloisine a is a cell-permeable pyrrolo-pyrazine compound that acts as a potent, selective, reversible, and ATP-competitive inhibitor of cyclin dependent kinases (Cdks: IC50 =150nM, 120 nM, 400 nM and 200 nM for Cdk1/cyclin B, Cdk2/cyclin A, Cdk2/cyclin E, and Cdk5/p25, respectively).
Purity:
≥98%
Appearance:
Yellow solid
Synonyms:
Aloisine A;4-(7-Butyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)phenol;
Solubility:
Soluble in DMSO
Storage:
Store at -20 °C
MSDS:
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Application:
A potent and selective CDK and GSK-3 inhibitor.
Quality Standard:
Enterprise Standard
Shelf Life:
As supplied, 2 years from the QC date provided on the Certificate of Analysis, when stored properly.
Quantity:
Milligrams-Grams
Melting Point:
151-153 °C
InChIKey:
AYIIQABSVDIZSY-UHFFFAOYSA-N
InChI:
1S/C16H17N3O/c1-2-3-4-13-14(11-5-7-12(20)8-6-11)19-16-15(13)17-9-10-18-16/h5-10,17H,2-4H2,1H3,(H,18,19)
Canonical SMILES:
CCCCC1=C2C(=NC=CN2)NC1=C3C=CC(=O)C=C3
1.Identification of potential cellular targets of aloisine A by affinity chromatography.
Corbel C1, Haddoub R, Guiffant D, Lozach O, Gueyrard D, Lemoine J, Ratin M, Meijer L, Bach S, Goekjian P. Bioorg Med Chem. 2009 Aug 1;17(15):5572-82. doi: 10.1016/j.bmc.2009.06.024. Epub 2009 Jun 18.
Affinity chromatography was used to identify potential cellular targets of aloisine A (7-n-butyl-6-(4'-hydroxyphenyl)-5H-pyrrolo[2,3b]pyrazine), a potent inhibitor of cyclin-dependent kinases. This technique is based on the immobilization of the drug on a solid matrix, followed by identification of specifically bound proteins. To this end, both aloisine A and the protein-kinase inactive control N-methyl aloisine, bearing extended linker chains have been synthesized. We present the preparation of such analogues having the triethylene glycol chain at different positions of the molecule, as well as their immobilization on an agarose-based matrix. Affinity chromatography of various biological extracts on the aloisine matrices allowed the identification of both protein kinases and non-kinase proteins as potential cellular targets of aloisine.
2.Compounds that target host cell proteins prevent varicella-zoster virus replication in culture, ex vivo, and in SCID-Hu mice.
Rowe J1, Greenblatt RJ, Liu D, Moffat JF. Antiviral Res. 2010 Jun;86(3):276-85. doi: 10.1016/j.antiviral.2010.03.007. Epub 2010 Mar 20.
Varicella-zoster virus (VZV) replicates in quiescent T cells, neurons, and skin cells. In cultured fibroblasts (HFFs), VZV induces host cyclin expression and cyclin-dependent kinase (CDK) activity without causing cell cycle progression. CDK1/cyclin B1 phosphorylates the major viral transactivator, and the CDK inhibitor roscovitine prevents VZV mRNA transcription. We investigated the antiviral effects of additional compounds that target CDKs or other cell cycle enzymes in culture, ex vivo, and in vivo. Cytotoxicity and cell growth arrest doses were determined by Neutral Red assay. Antiviral effects were evaluated in HFFs by plaque assay, genome copy number, and bioluminescence. Positive controls were acyclovir (400 microM) and phosphonoacetic acid (PAA, 1 mM). Test compounds were roscovitine, aloisine A, and purvalanol A (CDK inhibitors), aphidicolin (inhibits human and herpesvirus DNA polymerase), l-mimosine (indirectly inhibits human DNA polymerase), and DRB (inhibits casein kinase 2).
3.Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects.
Mettey Y1, Gompel M, Thomas V, Garnier M, Leost M, Ceballos-Picot I, Noble M, Endicott J, Vierfond JM, Meijer L. J Med Chem. 2003 Jan 16;46(2):222-36.
Cyclin-dependent kinases (CDKs) regulate the cell cycle, apoptosis, neuronal functions, transcription, and exocytosis. The observation of CDK deregulations in various pathological situations suggests that CDK inhibitors may have a therapeutic value. In this article, we report on the identification of 6-phenyl[5H]pyrrolo[2,3-b]pyrazines (aloisines) as a novel potent CDK inhibitory scaffold. A selectivity study performed on 26 kinases shows that aloisine A is highly selective for CDK1/cyclin B, CDK2/cyclin A-E, CDK5/p25, and GSK-3 alpha/beta; the two latter enzymes have been implicated in Alzheimer's disease. Kinetic studies, as well as the resolution of a CDK2-aloisine cocrystal structure, demonstrate that aloisines act by competitive inhibition of ATP binding to the catalytic subunit of the kinase. As observed with all inhibitors reported so far, aloisine interacts with the ATP-binding pocket through two hydrogen bonds with backbone nitrogen and oxygen atoms of Leu 83.
4.Proliferative and androgenic effects of indirubin derivatives in LNCaP human prostate cancer cells at sub-apoptotic concentrations.
Rivest P1, Renaud M, Sanderson JT. Chem Biol Interact. 2011 Feb 1;189(3):177-85. doi: 10.1016/j.cbi.2010.11.008. Epub 2010 Nov 25.
Certain indirubin derivatives are potent cyclin-dependent kinase (CDK) and glycogen synthase kinase (GSK-3β) inhibitors and may be effective against various cancers. We evaluated the effects of aloisine A, alsterpaullone, aminopurvalanol, indirubin-3'-oxime, 6-Br-indirubin-3'-oxime, kenpaullone, olomoucine and roscovitine on cell proliferation, prostate-specific antigen (PSA) expression, androgen receptor (AR) activation, and GSK-3β and β-catenin expression in androgen-dependent LNCaP human prostate cancer cells. Effects were also evaluated in MDA-kb2 human breast cancer cells containing an AR-responsive luciferase construct. Steroid-deprived LNCaP cells were exposed to indirubins±dihydrotestosterone (DHT, 0.1 nM) and cell proliferation was assessed by MTT assay after 120 h. PSA expression was determined by real-time quantitative RT-PCR after 24h. Cytoplasmic and nuclear GSK-3β/β-catenin expression and phosphorylation status was determined by Western blotting.
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Chemical Structure

CAS 496864-16-5 Aloisine A

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