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Suppression of Mast Cell Degranulation by a Novel Ceramide Kinase Inhibitor, the F-12509A Olefin Isomer K1

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Suppression of Mast Cell Degranulation by a Novel Ceramide Kinase Inhibitor, the F-12509A Olefin Isomer K1 Title Suppression of mast cell degranulation by a novel ceramide kinase inhibitor, the F-12509A olefin isomer K1 Kim, Jin-Wook; Inagaki, Yuichi; Mitsutake, Susumu; Maezawa, Nobuhiro; Katsumura, Shigeo; Ryu, Yeon-Woo; Park, Author(s) Chang-Seo; Taniguchi, Masaru; Igarashi, Yasuyuki Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1738(1-3), 82-90 Citation https://doi.org/10.1016/j.bbalip.2005.10.007 Issue Date 2005 Doc URL http://hdl.handle.net/2115/5800 Type article (author version) File Information BBA1738(1-3).pdf Instructions for use Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP 1 Suppression of mast cell degranulation by a novel ceramide kinase inhibitor, the F-12509A olefin isomer K1 Jin-Wook Kima, b, c, 1, Yuichi Inagakia, 1, Susumu Mitsutakea, Nobuhiro Maezawad, Shigeo Katsumurad, Yeon-Woo Ryub, Chang-Seo Parke, Masaru Taniguchif, and Yasuyuki Igarashia aDepartment of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Science, Hokkaido University. Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan, bDepartment of Molecular Science and Technology, Ajou University, San 5, Wonchun-dong, Yeongtong-gu, Suwon 443-749, Korea, cDoosan Biotech, 39-3, Seongbok-dong, Yongin-si, Gyeonggi-do 449-795, Korea, dSchool of Science and Technology, Kwansei Gakuin University, Gakuen, Sanda, Hyogo 669-1337, Japan, eDepartment of Chemical and Biochemical Engineering, Dongguk University, 3-26 Pil-dong, Chung-gu, Seoul 100-715, Korea, fRIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan Key words: ceramide, ceramide 1-phosphate, ceramide kinase, inhibitor, degranulation, mast cell To whom correspondence should be addressed: Dr. Yasuyuki Igarashi Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Science, Hokkaido University. Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan. Phone: 81-11-706-3970 Fax: 81-11-706-4986 Email address : [email protected] 1 2 Abstract 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 Ca2+ mobilization. Finally, we show that K1 affects neither IgE/antigen-induced global tyrosine phosphorylation nor subsequent Ca2+ 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. 1. Introduction Antigen-induced aggregation of IgE receptor (FcεRI) in mast cells plays a pivotal role in allergic and inflammatory responses. Aggregation of this receptor prompts the recruitment and activation of cytosolic tyrosine kinases and phospholipases (1,2). These cellular events culminate in the exocytosis of granular content and subsequent allergic inflammation, such as that associated with asthma and anaphylaxis. Therefore, regulation of mast cell degranulation is a potential target for anti-allergic therapeutics. 2 3 The breakdown of sphingomyelin (SM) produces bioactive sphingolipid metabolites, including ceramide (CER), sphingosine (SPH), and sphingosine 1-phosphate (S1P). These sphingolipid metabolites play important roles in the regulation of cell proliferation, survival and apoptosis (3-5). In particular, S1P has been implicated as a key factor in modulating mast cells (6), and ceramide 1-phosphate (C1P), which is formed via the phosphorylation of CER by ceramide kinase (CERK), is emerging as an important mediator in mast cell degranulation (7,8). Both CERK and C1P have also been implicated in the regulation of neurotransmitter secretion, theoretically by increasing the fusibility of the vesicle membranes (9), and C1P promotes phagolysosome formation and liposome fusion (10,11). These studies have identified C1P as a potent mediator for membrane fusion. C1P induces cellular arachidonic acid release in A549 lung adenocarcinoma cells via activation of phospholipase A2 (12). Human CERK was recently cloned based on its sequence homology to sphingosine kinase type 1 (SPHK1) (13). CERK has an N-terminal plecstrin homology (PH) domain and a C-terminal Ca2+/calmodulin binding domain, and is activated by Ca2+ (9). Furthermore, the Ca2+/calmodulin binding domain is essential for the Ca2+-induced activation (14). Such an increase in CERK activity, attributable to elevations in intracellular Ca2+ levels, has been observed in rat basophilic leukemia cells following IgE/antigen treatment (7). Moreover, both the calcium-induced CERK activation and the formation of C1P were found to be necessary steps in calcium ionophore-induced mast cell degranulation (7). Some sphingosine kinase inhibitors are known to modestly inhibit CERK at high concentrations in vitro (13). However, to date, no specific and effective CERK inhibitor has been reported. Although C2-ceramide has been used to inhibit CERK activity (7), it is also known to inhibit protein kinase C and IgE/antigen-induced phospholipase D (PLD) activation (15-17). Furthermore, C2-ceramide is unsuitable as a therapeutic tool for allergic diseases, because of its high cytotoxicity (18). In our search of novel CERK inhibitors, we have developed analogs of F-12509A, a 3 4 previously reported SPHK inhibitor (19). We have identified an olefin isomer of F-12509A that effectively and specifically inhibits CERK activity. Furthermore, this new CERK inhibitor suppresses RBL-2H3 mast cell degranulation, suggesting that this and other CERK inhibitors could be a potent therapeutic tool for allergic diseases. 2. Materials and methods 2. 1. Synthesis and characterization of F-12509A and its analogs (Scheme 1, 2) Alcohol 3 To a solution of acetonide 3 (1.388 g, 6.244 mmol) in tetrahydrofuran (30 mL) was added dropwise n-butyl lithium (1.6 M solution in hexane, 5.5 mL, 8.742 mmol) at -10 oC. The reaction mixture was stirred at -10 oC for an additional 30 min then gradually warmed to room temperature. The mixture was stirred for 2 h, and albicanal 2 (688 mg, 3.112 mmol) in tetrahydrofuran (15 mL) was added at room temperature. After the mixture was stirred for 45 min at room temperature, a saturated aqueous NH4Cl solution was added. The resulting mixture was extracted with diethyl ether. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude products, which were purified by column chromatography on silica gel (from 0.5% to 20% ethyl acetate in hexane) resulting in alcohol 4 (2.128 g, 77%) as a pale yellow solid: IR -1 1 (KBr disk, cm ) 3594, 2930, 2866, 1466, 1211, 1161, 837; H NMR (CDCl3, 400 MHz) δ 6.23 (s, 1H), 5.22 (dd, J = 6.4, 4.6 Hz, 1H), 4.69 (s, 1H), 4.62 (s, 1H), 2.70 (d, J = 4.6 Hz, 1H), 2.47 (d, J = 6.1 Hz, 1H), 2.37 (m, 1H), 2.05-2.15 (m, 1H), 1.90 (m, 1H), 1.72 (m, 2H), 1.61 (s, 12H), 1.45 (m, 1H), 1.42 13 (m, 1H), 1.40 (m, 2H), 1.30 (m, 1H), 1.03 (s, 3H), 1.00 (s, 3H), 0.81 (s, 3H); C NMR (CDCl3, 100 MHz) δ 147.6, 140.3, 137.8, 117.8, 108.2, 91.4, 66.6, 60.4, 59.9, 42.1, 39.0, 38.7, 33.6, 25.7, 25.6, + 25.1, 24.7, 22.8, 22.3, 21.8, 19.3; ESI HRMS m/z calcd for C27H38O5 [M + Na] 465.2617, found 4 5 465.2615. Xanthate 5 To a solution of alcohol 4 (2.479 g, 5.601 mmol) in tetrahydrofuran (28 mL) was added dropwise sodium bis(tirmethylsily)amide (1.0 M solution in tetrahydrofuran, 16.8 mL, 16.803 mmol) at -78 oC. The reaction mixture was stirred for 30 min at -78 oC and carbon disulfide (2.36 mL, 39.207 mmol) was added at the same temperature. The mixture was gradually warmed to -40 oC for 1 h, and then methyl iodide (3.53 mL, 56.010 mmol) was added at -78 oC. After the mixture was o gradually warmed to 0 C for 2 h, saturated aqueous Na2SO3 solution was added. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude xanthate 5, which was used without further purification. Acetonide 6 To a solution of xanthate 5 in benzene (50 mL) was added tributyltin hydride (6.7 mL, 24.910 mmol) and 2,2’-azobisisobutyronitrile (82 mg, 0.498 mmol) at room temperature. After the reaction mixture was stirred for 3 h under reflux conditions, the solution was cooled at room temperature. The solvent was removed in vacuo, yielding a crude product. Column chromatography on silica gel (from 0% to 3% ethyl acetate in hexane) yielded the corresponding acetonide 6 (2.807 g, 87%) as a white solid: IR (KBr disk, cm-1) 2936, 2866, 1719, 1647, 1462, 1211, 1161, 841; 1H NMR (CDCl3, 400 MHz) δ 6.14 (s, 1H), 4.70 (s, 1H), 4.69 (s, 1H), 2.68 (dd, J = 13.9, 2.9 Hz, 2H), 2.51 (m, 2H), 2.31 (ddd, J = 13.9, 4.2, 2.4 Hz, 1H), 1.92 (dt, J = 12.7, 4.9 Hz, 1H), 1.79 (br-d, J = 14.0 Hz, 1H), 1.65-1.77 (m, 2H), 1.61 (s, 12H), 1.56 (d, J = 9.0 Hz, 2H), 1.50 (dt, J = 14.0, 3.6 Hz, 1H), 1.38 (m, 1H), 1.30 (m, 1H), 1.25 (m, 1H), 1.15 (dd, J = 12.7, 2.9 Hz, 1H), 0.86 (s, 3H), 0.83 (s, 3H), 0.77 (s, 13 3H); C NMR (CDCl3, 100 MHz) δ 148.4, 139.8, 139.2, 117.0, 108.9, 106.6, 90.0, 55.6, 54.2, 42.2, 38.9, 38.9, 38.3, 33.6, 27.8, 26.8, 25.6, 24.5, 21.8, 19.5, 17.5, 14.1, 13.6; ESI HRMS m/z calcd for 5 6 + C27H38O4 [M] 426.2770, found 426.2780.
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