Phospholipases A2 (PLA2s) are enzymes that are capable of catalyzing the hydrolysis of the sn-2 ester bond of glycerophospholipids, releasing free fatty acids, including arachidonic acid (AA), and lysophospholipids. Both products are precursor signaling molecules involved in inflammation. Among the various PLA2s, cytosolic GIVA cPLA2 is considered a major target for inflammatory diseases, while secreted GIIA sPLA2 is involved in cardiovascular diseases. We have developed lipophilic 2-oxoamides based on (S)-γ- or δ-amino acids as potent and selective inhibitors of GIVA cPLA2, which present interesting in vivo anti-inflammatory activity. 2-Oxoamides based on natural α-amino acids are selective inhibitors of GIIA sPLA2. The mode of binding of 2-oxoamides with either GIVA cPLA2 or GIIA sPLA2 has been studied by various techniques.
Conference
IUPAC Congress, IUPAC Congress, CONGRESS, IUPAC Congress, 43rd, San Juan, Puerto Rico, 2011-07-30–2011-08-07
References
1 10.1021/cr200085w, E. A. Dennis, J. Cao, Y.-H. Hsu, V. Magrioti, G. Kokotos. Chem. Rev.111, 6130 (2011).Search in Google Scholar
2 10.1126/science.294.5548.1871, C. D. Funk. Science294, 1871 (2001).Search in Google Scholar
3 10.1007/112_0507, R. Rivera, J. Chun. Rev. Physiol. Biochem. Pharmacol.160, 25 (2008).Search in Google Scholar
4 10.1002/ejlt.200800249, G. Kokotos. Eur. J. Lipid Sci. Technol.110, 1081 (2008).Search in Google Scholar
5 10.1517/13543770903463905, V. Magrioti, G. Kokotos. Expert Opin. Ther. Patents20, 1 (2010).Search in Google Scholar
6 V. Magrioti, G. Kokotos. Antiinflammatory Antiallergy Agents Med. Chem.5, 189 (2006).Search in Google Scholar
7 M. Lehr. Antiinflammatory Antiallergy Agents Med. Chem.5, 149 (2006).Search in Google Scholar
8 10.2174/092986705774462860, R. C. Reid. Curr. Med. Chem.12, 3011 (2005).Search in Google Scholar
9 10.1016/0092-8674(91)90556-E, J. D. Clark, L.-L. Lin, R. W. Kriz, C. S. Ramesha, L. A. Sultzman, A. Y. Lin, N. Milona, J. L. Knopf. Cell65, 1043 (1991).Search in Google Scholar
10 R. M. Kramer, E. F. Roberts, J. Manetta, J. E. Putnam. J. Biol. Chem.266, 5268 (1991).Search in Google Scholar
11 10.1016/j.biochi.2010.03.001, C. C. Leslie, T. A. Gangelhoff, M. H. Gelb. Biochimie92, 620 (2010).Search in Google Scholar
12 10.1016/S0092-8674(00)80744-8, A. J. Dessen, J. Tang, H. Schmidt, M. Stahl, J. D. Clark, J. Seehra, W. S. Somers. Cell97, 349 (1999).Search in Google Scholar
13 J. D. Sharp, R. T. Pickard, X. G. Chiou, J. V. Manetta, S. Kovacevic, J. R. Miller, A. D. Varshavsky, E. F. Roberts, B. A. Strifler, D. N. Brems. J. Biol. Chem.269, 23250 (1994).Search in Google Scholar
14 10.1021/bi952541k, Z. Huang, P. Fayette, K. Abdullah, W. A. Cromlish, B. P. Kennedy. Biochemistry35, 3712 (1996).Search in Google Scholar PubMed
15 10.1074/jbc.273.1.207, P. K. Larsson, H. E. Claesson, B. P. Kennedy. J. Biol. Chem.273, 207 (1998).Search in Google Scholar
16 E. J. Ackermann, E. S. Kempner, E. A. Dennis. J. Biol. Chem.269, 9227 (1994).Search in Google Scholar
17 J. Tang, R. W. Kriz, N. Wolfman, M. Shaffer, J. Seehra, S. S. Jones. J. Biol. Chem.272, 8567 (1997).Search in Google Scholar
18 J. Seilhamer, W. Pruzanski, P. Vadas, S. Plant, J. A. Miller, J. Kloss, L. K. Johnson. J. Biol. Chem.264, 5335 (1989).Search in Google Scholar
19 10.1111/j.1742-4658.2004.04489.x, S. Masuda, M. Murakami, K. Komiyama, M. Ishihara, Y. Ishikawa, T. Ishii, I. Kudo. FEBS J.272, 655 (2005).Search in Google Scholar
20 10.1021/cr990139w, O. G. Berg, M. H. Gelb, M.-D. Tsai, M. K. Jain. Chem. Rev.101, 2613 (2001).Search in Google Scholar
21 10.1074/jbc.M804750200, U. Samanta, B. J. Bahnson. J. Biol. Chem.283, 31617 (2008).Search in Google Scholar
22 10.1016/S0090-6980(02)00021-7, N. Uozumi, T. Shimizu. Prostaglandins Other Lipid Mediators68–69, 59 (2002).Search in Google Scholar
23 10.1038/37635, J. V. Bonventre, Z. Huang, M. R. Taheri, E. O’Leary, E. Li, M. A. Moskowitz, A. Sapirstein. Nature390, 622 (1997).Search in Google Scholar PubMed
24 D. H. Adler, J. D. Cogan, J. A. Phillips 3rd, N. Schnetz-Boutaud, G. L. Milne, T. Iverson, J. A. Stein, D. A. Brenner, J. D. Morrow, O. Boutaud, J. A. Oates. J. Clin. Invest.118, 2121 (2008).Search in Google Scholar
25 N. Uozumi, K. Kume, T. Nagase, N. Nakatani, S. Ishii, F. Tashiro, Y. Komagata, K. Maki, K. Ikuta, Y. Ouchi, J.-I. Miyazaki, T. Shimizu. Nature390, 618 (1997).10.1038/37622Search in Google Scholar PubMed
26 T. Nagase, N. Uozumi, S. Ishii, K. Kume, T. Izumi, Y. Ouchi, T. Shimizu. Nat. Immunol.1, 42 (2000).Search in Google Scholar
27 10.1158/1078-0432.CCR-08-0566, M. I. Patel, J. Singh, M. Niknami, C. Kurek, M. Yao, S. Lu, F. Maclean, N. J. King, M. H. Gelb, K. F. Scott, P. J. Russell, J. Boulas, Q. Dong. Clin. Cancer Res.14, 8070 (2008).Search in Google Scholar PubMed PubMed Central
28 10.1038/nn.2213, R. O. Sanchez-Mejia, J. W. Newman, S. Toh, G.-Q. Yu, Y. Zhou, B. Halabisky, M. Cissé, K. Scearce-Levie, I. H. Cheng, L. Gan, J. J. Palop, J. V. Bonventre, L. Mucke. Nat. Neurosci.11, 1311 (2008).Search in Google Scholar PubMed PubMed Central
29 10.1016/j.cellsig.2005.03.002, J. Balsinde, M. A. Balboa. Cell. Signalling17, 1052 (2005).Search in Google Scholar PubMed
30 J. Balsinde, R. Perez, M. A. Balboa. Biochim. Biophys. Acta1761, 1344 (2006).10.1016/j.bbalip.2006.07.013Search in Google Scholar PubMed
31 10.1016/j.bcp.2008.07.044, S. B. Hooks, B. S. Cummings. Biochem. Pharmacol.76, 1059 (2008).Search in Google Scholar PubMed PubMed Central
32 10.2174/138945008785132385, W. P. Wilkins, S. E. Barbour Curr. Drug Targets9, 683 (2008).Search in Google Scholar PubMed
33 10.1021/bi035536m, S. Ramanadham, F. F. Hsu, S. Zhang, C. Jin, A. Bohrer, H. Song, S. Bao, Z. Ma, J. Turk. Biochemistry43, 918 (2004).Search in Google Scholar PubMed PubMed Central
34 10.1074/jbc.M406489200, S. Bao, D. J. Miller, Z. Ma, M. Wohltmann, G. Eng, S. Ramanadham, K. Moley, J. Turk. J. Biol. Chem.279, 38194 (2004).Search in Google Scholar PubMed PubMed Central
35 10.2353/ajpath.2008.070756, S. Ramanadham, K. E. Yarasheski, M. J. Silva, M. Wohltmann, D. V. Novack, B. Christiansen, X. Tu, S. Zhang, X. Lei, J. Turk. Am. J. Pathol.172, 868 (2008).Search in Google Scholar PubMed PubMed Central
36 10.1146/annurev.biochem.76.062405.154007, G. Lambeau, M. H. Gelb. Annu. Rev. Biochem.77, 495 (2008).Search in Google Scholar PubMed
37 10.1007/s10557-008-6134-7, B. B. Boyanovsky, N. R. Webb. Cardiovasc. Drugs Ther.23, 61 (2009).Search in Google Scholar PubMed PubMed Central
38 10.1093/jb/mvr088, M. Murakami, Y. Taketomi, H. Sato, K. Yamamoto. J. Biochem.150, 233 (2011).Search in Google Scholar PubMed
39 B. Balestrieri, J. P. Arm. Biochim. Biophys. Acta1761, 1280 (2006).10.1016/j.bbalip.2006.07.008Search in Google Scholar PubMed
40 B. Rosengren, A.-C. Jonsson-Rylander, H. Peilot, G. Camejo, E. Hurt-Camejo. Biochim. Biophys. Acta1761, 1301 (2006).10.1016/j.bbalip.2006.06.008Search in Google Scholar PubMed
41 10.1016/j.atherosclerosis.2006.08.062, M. Kimura-Matsumoto, Y. Ishikawa, K. Komiyama, T. Tsuruta, M. Murakami, S. Masuda, Y. Akasaka, K. Ito, S. Ishiguro, H. Morita, S. Sato, T. Ishii. Atherosclerosis196, 81 (2008).Search in Google Scholar PubMed
42 10.1074/jbc.M202867200, K. Hanasaki, K. Yamada, S. Yamamoto, Y. Ishimoto, A. Saiga, T. Ono, M. Ikeda, M. Notoya, S. Kamitani, H. Arita. J. Biol. Chem.277, 29116 (2002).Search in Google Scholar PubMed
43 10.1161/01.ATV.0000122363.02961.c1, C. R. Wooton-Kee, B. B. Boyanovsky, M. S. Nasser, W. J. S. de Villiers, N. R. Webb. Arterioscler. Thromb. Vasc. Biol.24, 762 (2004).Search in Google Scholar PubMed
44 10.1096/fj.06-6018fje, S.-A. Karabina, I. Brocheriou, G. Le Naour, M. Agrapart, H. Durand, M. Gelb, G. Lambeau, E. Ninio. FASEB J.20, 2547 (2006).Search in Google Scholar PubMed
45 10.1161/01.ATV.0000257133.60884.44, M. A. Bostrom, B. B. Boyanovsky, C. T. Jordan, M. P. Wadsworth, D. J. Taatjes, F. C. de Beer, N. R. Webb. Arterioscler. Thromb. Vasc. Biol.27, 600 (2007).Search in Google Scholar PubMed
46 10.1084/jem.20070029, W. R. Henderson, E. Y. Chi, J. G. Bollinger, Y.-T. Tien, X. Ye, L. Castelli, Y. P. Rubtsov, A. G. Singer, G. K. S. Chiang, T. Nevalainen, A. Y. Rudensky, M. H. Gelb. J. Exp. Med.204, 865 (2007).Search in Google Scholar PubMed PubMed Central
47 10.1021/jm025538p, G. Kokotos, S. Kotsovolou, D. A. Six, V. Constantinou-Kokotou, C. C. Beltzner, E. A. Dennis. J. Med. Chem.45, 2891 (2002).Search in Google Scholar PubMed
48 10.1021/jm030485c, G. Kokotos, D. A. Six, V. Loukas, T. Smith, V. Constantinou-Kokotou, D. Hadjipavlou-Litina, S. Kotsovolou, A. Chiou, C. C. Beltzner, E. A. Dennis. J. Med. Chem.47, 3615 (2004).Search in Google Scholar PubMed
49 10.1021/jm050993h, D. Stephens, E. Barbayianni, V. Constantinou-Kokotou, A. Peristeraki, D. A. Six, J. Cooper, R. Harkewicz, R. A. Deems, E. A. Dennis, G. Kokotos. J. Med. Chem.49, 2821 (2006).Search in Google Scholar PubMed PubMed Central
50 10.1016/j.bmc.2008.10.046, G. Antonopoulou, E. Barbayianni, V. Magrioti, N. Cotton, D. Stephens, V. Constantinou-Kokotou, E. A. Dennis, G. Kokotos. Bioorg. Med. Chem.16, 10257 (2008).Search in Google Scholar
51 K. Lee, D.-K. Kim. J. Kor. Chem. Soc.48, 161 (2004).Search in Google Scholar
52 10.1021/jm0613673, D. A. Six, E. Barbayianni, V. Loukas, V. Constantinou-Kokotou, D. Hadjipavlou-Litina, D. Stephens, A. C. Wong, V. Magrioti, P. Moutevelis-Minakakis, S. F. Baker, E. A. Dennis, G. Kokotos. J. Med. Chem.50, 4222 (2007).Search in Google Scholar
53 10.1002/psc.628, V. Constantinou-Kokotou, A. Peristeraki, C. G. Kokotos, D. A. Six, E. A. Dennis. J. Peptide Sci.11, 431 (2005).Search in Google Scholar
54 10.1093/brain/awp002, A. Kalyvas, C. Baskakis, V. Magrioti, V. Constantinou-Kokotou, D. Stephens, R. López-Vales, J.-Q. Lu, V. Wee Yong, E. A. Dennis, G. Kokotos S. David. Brain132, 1221 (2009).Search in Google Scholar
55 10.1096/fj.11-183186, R. López-Vales, N. Ghasemlou, A. Redensek, B. J. Kerr, E. Barbayianni, G. Antonopoulou, C. Baskakis, K. I. Rathore, V. Constantinou-Kokotou, D. Stephens, T. Shimizu, E. A. Dennis, G. Kokotos, S. David. FASEB J.25, 4240 (2011).Search in Google Scholar
56 10.1016/S0896-6273(04)00003-0, A. Kalyvas, S. David. Neuron41, 323 (2004).Search in Google Scholar
57 10.1007/978-3-7091-0651-8_36, S. Tabuchi, N. Uozumi, S. Ishii, Y. Shimizu, T. Watanabe, T. Shimizu. Acta Neurochir.86, 169 (2003).Search in Google Scholar PubMed
58 10.1046/j.0953-816x.2001.01623.x, K. Arai, Y. Nakatani, I. Kudo, N. Nishiyama, N. Matsuki. Eur. J. Neurosci.13, 2319 (2001).Search in Google Scholar PubMed
59 10.1124/jpet.105.091686, T. L. Yaksh, G. Kokotos, C. I. Svensson, D. Stephens, C. G. Kokotos, B. Fitzsimmons, D. Hadjipavlou-Litina, X.-Y. Hua, E. A. Dennis. J. Pharm. Exp. Ther.316, 466 (2006).Search in Google Scholar PubMed
60 10.1016/j.bmc.2009.03.069, E. Barbayianni, D. Stephens, A. Grkovich, V. Magrioti, Y.-H. Hsu, P. Dolatzas, D. Kalogiannidis, E. A. Dennis, G. Kokotos. Bioorg. Med. Chem.17, 4833 (2009).Search in Google Scholar PubMed PubMed Central
61 10.1002/psc.1048, G. Antonopoulou, V. Magrioti, D. Stephens, V. Constantinou-Kokotou, E. A. Dennis, G. Kokotos. J. Pept. Sci.14, 1111 (2008).Search in Google Scholar PubMed PubMed Central
62 10.1002/psc.889, P. Moutevelis-Minakakis, A. Neokosmidi, M. Filippakou, D. Stephens, E. A. Dennis, G. Kokotos. J. Pept. Sci.13, 634 (2007).Search in Google Scholar PubMed
63 10.1016/j.bmc.2010.12.030, V. D. Mouchlis, V. Magrioti, E. Barbayianni, N. Cermak, R. C. Oslund, T. M. Mavromoustakos, M. H. Gelb, G. Kokotos. Bioorg. Med. Chem.19, 735 (2011).Search in Google Scholar PubMed PubMed Central
64 10.2174/092986711795933678, V. D. Mouchlis, E. Barbayianni, T. M. Mavromoustakos, G. Kokotos. Curr. Med. Chem.18, 2566 (2011).Search in Google Scholar PubMed
65 10.1021/ja900098y, J. E. Burke, A. Babakhani, A. A. Gorfe, G. Kokotos, S. Li, V. L. Woods Jr., J. A. McCammon, E. A. Dennis. J. Am. Chem. Soc.131, 8083 (2009).Search in Google Scholar PubMed PubMed Central
© 2013 Walter de Gruyter GmbH, Berlin/Boston
