F-12509A
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| Category | Enzyme inhibitors |
| Catalog number | BBF-02832 |
| CAS | 191608-64-7 |
| Molecular Weight | 344.44 |
| Molecular Formula | C21H28O4 |
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Description
It is produced by the strain of Trichopezizella barbata SANK 25395. F-12509A has competitive inhibitory activity against sphingosine kinase, and the Ki value is 18μmol/L.
Specification
| Synonyms | F12509A |
| IUPAC Name | 3-[[(1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]methyl]-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione |
| Canonical SMILES | CC1(CCCC2(C1CCC(=C)C2CC3=C(C(=O)C=C(C3=O)O)O)C)C |
| InChI | InChI=1S/C21H28O4/c1-12-6-7-17-20(2,3)8-5-9-21(17,4)14(12)10-13-18(24)15(22)11-16(23)19(13)25/h11,14,17,22,25H,1,5-10H2,2-4H3/t14-,17-,21+/m0/s1 |
| InChI Key | KFAYECQGXSDHKU-XXHMAFKTSA-N |
Properties
| Appearance | Pale Yellow Powder |
Reference Reading
1. Suppression of mast cell degranulation by a novel ceramide kinase inhibitor, the F-12509A olefin isomer K1
Jin-Wook Kim, Yuichi Inagaki, Susumu Mitsutake, Nobuhiro Maezawa, Shigeo Katsumura, Yeon-Woo Ryu, Chang-Seo Park, Masaru Taniguchi, Yasuyuki Igarashi Biochim Biophys Acta. 2005 Dec 30;1738(1-3):82-90. doi: 10.1016/j.bbalip.2005.10.007. Epub 2005 Nov 14.
Antigen-induced degranulation of mast cells plays a pivotal role in allergic and inflammatory responses. Recently, ceramide kinase (CERK) and its phosphorylated product ceramide 1-phosphate (C1P) have emerged as important players in mast cell degranulation. Here, we describe the synthesis of a novel F-12509A olefin isomer, K1, as an effective CERK inhibitor. In vitro kinase assays demonstrated that K1 effectively inhibits CERK without inhibiting sphingosine kinase and diacylglycerol kinase. Treating RBL-2H3 cells with K1 reduced cellular C1P levels to 40% yet had no effect on cell growth. Furthermore, treatment with K1 significantly suppressed both calcium ionophore- and IgE/antigen-induced degranulation, indicating that K1 interferes with signals that happen downstream of Ca(2+) mobilization. Finally, we show that K1 affects neither IgE/antigen-induced global tyrosine phosphorylation nor subsequent Ca(2+) elevation, suggesting a specificity for CERK-mediated signals. Our novel CERK inhibitor provides a useful tool for studying the biological functions of CERK and C1P. Moreover, to our knowledge, this is the first report demonstrating that inhibition of CERK suppresses IgE/antigen-induced mast cell degranulation. This finding suggests that CERK inhibitors might be a potential therapeutic tool in the treatment of allergic diseases.
2. Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells
E Bonhoure, A Lauret, D J Barnes, C Martin, B Malavaud, T Kohama, J V Melo, O Cuvillier Leukemia. 2008 May;22(5):971-9. doi: 10.1038/leu.2008.95. Epub 2008 Apr 10.
We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and -resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and -resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the Bcr-Abl/Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members.
3. Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1
E Bonhoure, D Pchejetski, N Aouali, H Morjani, T Levade, T Kohama, O Cuvillier Leukemia. 2006 Jan;20(1):95-102. doi: 10.1038/sj.leu.2404023.
We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrug-resistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60NP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/ Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the pre-mitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 over-expression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
