作用于炎症小体的α,β-不饱和酮类化合物的合成及活性评价

doi:10.5246/jcps.2018.05.031

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (5): 295-306.DOI: 10.5246/jcps.2018.05.031

• 【研究论文】 • 下一篇

作用于炎症小体的α,β-不饱和酮类化合物的合成及活性评价

孔秋云¹, 杭楠², 张超¹, 李树春¹, 李中军¹, 孙洋^2*, 孟祥豹^1,2*

1. 北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191
2. 南京大学生命科学院医药生物技术国家重点实验室, 江苏南京 210023

收稿日期:2018-01-11 修回日期:2018-04-17 出版日期:2018-05-31 发布日期:2018-05-02
通讯作者: Tel.: +86-010-82801714, E-mail: xbmeng@bjmu.edu.cn; sunyangnju@163.com
基金资助:
The National Natural Science Foundation of China (Grant No. 81573272).

Synthesis and biological evaluation of α,β-unsaturated carbonyl compounds targeting the NLRP3 inflammasome

Qiuyun Kong¹, Nan Hang², Chao Zhang¹, Shuchun Li¹, Zhongjun Li¹, Yang Sun^2*, Xiangbao Meng^1,2*

1. State Key Laboratory of Natural and Biomimetic Drugs; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China

Received:2018-01-11 Revised:2018-04-17 Online:2018-05-31 Published:2018-05-02
Contact: Tel.: +86-010-82801714, E-mail: xbmeng@bjmu.edu.cn; sunyangnju@163.com
Supported by:
The National Natural Science Foundation of China (Grant No. 81573272).

摘要/Abstract

摘要：

以NLRP3炎症小体为靶点,设计并合成了一系列α,β-不饱和酮类化合物,并测定了其体外抗炎活性。发现数个化合物有强的抑制IL-1β释放的抗炎活性,其中A21表现出最强的抗炎活性,并呈剂量依赖关系,其IC₅₀为0.95μM。论文中还总结了该类化合物初步的构效关系。

关键词: α,β-不饱和酮, 炎症小体, IL-1β, 抗炎活性

Abstract:

A series of α,β-unsaturated ketone derivatives were synthesized, and their anti-inflammatory activity toward NLRP3 inflammasome was evaluated in vitro. Several compounds were identified as anti-inflammatory agents, among which compound A21 exhibited potent anti-inflammatory activity in a dose-dependent manner with an IC₅₀ of 0.95 μM. Moreover, a preliminary structure-activity relationship was also summarized.

Key words: a,β-Unsaturated ketone, NLRP3, IL-1β, Anti-inflammatory

中图分类号:

R916

Supporting:

孔秋云, 杭楠, 张超, 李树春, 李中军, 孙洋, 孟祥豹. 作用于炎症小体的α,β-不饱和酮类化合物的合成及活性评价[J]. 中国药学(英文版), 2018, 27(5): 295-306.

Qiuyun Kong, Nan Hang, Chao Zhang, Shuchun Li, Zhongjun Li, Yang Sun, Xiangbao Meng. Synthesis and biological evaluation of α,β-unsaturated carbonyl compounds targeting the NLRP3 inflammasome[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(5): 295-306.

参考文献

[1] Takeuchi, O.; Akira, S. Pattern recognition receptors and inflammation. Cell. 2010, 140, 805-820.

[2] Rock, K.L.; Latz, E.; Ontiveros, F.; Kono, H. The sterile inflammatory response. Annu. Rev. Immunol. 2010, 28, 321-342.

[3] Franchi, L.; Muñoz-Planillo, R.; Núñez, G. Sensing and reacting to microbes through the inflammasomes. Nat. Immunol. 2012, 13, 325-332.

[4] Martinon, F.; Pétrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006, 440, 237-241.

[5] Hornung, V.; Bauernfeind, F.; Halle, A.; Samstad, E.O.; Kono, H.; Rock, K.L.; Fitzgerald, K.A.; Latz, E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 2008, 9, 847-856.

[6] Duewell, P.; Kono, H.; Rayner, K.J.; Sirois, C.M.; Vladimer, G.; Bauernfeind, F.G.; Abela, G.S.; Franchi, L.; Nuñez, G.; Schnurr, M.; Espevik, T.; Lien, E.; Fitzgerald, K.A.; Rock, K.L.; Moore, K.J.; Wright, S.D.; Hornung, V.; Latz, E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010, 464, 1357-1361.

[7] Lee, H.M.; Kim, J.J.; Kim, H.J.; Shong, M.; Ku, B.J.; Jo, E.K. Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes. Diabetes. 2013, 62, 194-204.

[8] Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 2008, 9, 857-865.

[9] Latz, E.; Xiao, T.S.; Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 2013, 13, 397-411.

[10] Yu, H.B.; Finlay, B.B. The Caspase-1 Inflammasome: A Pilot of Innate Immune. Cell Host Microbe. 2008, 4, 198-208.

[11] Locovei, S.; Scemes, E.; Qiu, F.; Spray, D.C.; Dahl, G. Pannexin1 is part of the pore forming unit of the P2X7 receptor death complex. FEBS Lett. 2007, 581, 483-488.

[12] Munoz-Planillo, R.; Kuffa, P.; Martinez-Colon, G.; Smith, B.L.; Rajendiran, T.M.; Nunez, G. K+ Efflux Is the Common Trigger of NLRP3 Inflammasome Activation by Bacterial Toxins and Particulate Matter. Immunity. 2013, 38, 1142-1153.

[13] Martinon, F.; Mayor, A.; Tschopp, J. The Inflammasomes: Guardians of the Body. Annu. Rev. Immunol. 2009, 27, 229-265.

[14] Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011, 469, 221-225.

[15] Py, B.F.; Kim, M.S.; Vakifahmetoglu-Norberg, H.; Yuan, J. Deubiquitination of NLRP3 by BRCC3 Critically Regulates Inflammasome Activity. Mol. Cell. 2013, 49, 331-338.

[16] Galea, J.; Ogungbenro, K.; Hulme, S.; Greenhalgh, A.; Aarons, L.; Scarth, S.; Hutchinson, P.; Grainger, S.; King, A.; Hopkins, S.J.; Rothwell, N.; Tyrrell, P. Intravenous Anakinra can Achieve Experimentally Effective Concentrations in the Central Nervous System within a Therapeutic Time Window: Results of a Dose-Ranging Study. J. Cereb. Blood Flow Metab. 2011, 31, 439-447.

[17] Fox, E.; Jayaprakash, N.; Pham, T.H.; Rowley, A. McCully, C.L.; Pucino, F.; Goldbach-Mansky, R. The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates. J. Neuroimmunol. 2010, 223, 138-140.

[18] Martinon, F.; Burns, K. Tschopp, The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. J. Mol. Cell. 2002, 10, 417-426.

[19] Kean, W.F.; Hart, L.; Buchanan W.W. Aurnaofin. Rheumatology. 1997, 36, 560-572.

[20] He, Y.; Varadarajan, S.; Muñoz-Planillo, R.; Burberry, A.; Nakamura, Y.; Núñez, G. 3,4-Methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J. Biol. Chem. 2014, 289, 1142-1150.

[21] Juliana, C.; Fernandes-Alnemri, T.; Wu, J.; Datta, P.; Solorzano, L.; Yu, J.W.; Meng, R.; Quong, A.A.; Latz, E.; Scott, C.P.; Alnemri, E.S. Anti-inflammatory Compounds Parthenolide and Bay 11-7082 Are Direct Inhibitors of the Inflammasome. J. Biol. Chem. 2010, 285, 9792-9802.

[22] Gong, Y.N.; Wang, X.; Wang, J.; Yang, Z.; Li, S.; Yang, J.; Liu, L.; Lei, X.; Shao, F. Chemical probing reveals insights into the signaling mechanism of inflammasome activation. Cell Res. 2010, 20, 1289-1305.

[23] Coll, R.C.; Robertson, A.A.B.; Chae, J.J.; Higgins, S.C.; Muñoz-Planillo, R.; Inserra, M.C.; Vetter, I.; Dungan, L.S.; Monks, B.G.; Stutz, A.; Croker, D.E.; Bulter, L.S.; Haneklaus, M.; Sutton, C.E.; Núñez, G.; Latz, E.; Kastner, D.L.; Mills, K.H.G.; Masters, S.L.; Schroder, K.; Cooper, M.A.; O’Neill, L.A.G. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 2015. 21, 248-255.

[24] Stierle, D.B.; Stierle, A.A.; Patacini, B.; Mclntyre, K.; Girtsman, T.; Bolstad, E. Berkeleyones and Related Meroterpenes from a Deep Water Acid Mine Waste Fungus That Inhibit the Production of Interleukin 1-β from Induced Inflammasomes. J. Nat. Prod. 2011, 74, 2273-2277.

[25] Liu, W.; Guo, W.; Wu, J.; Luo, Q.; Tao, F.; Gu, Y.; Shen, Y.; Li, J.; Tan, R.; Xu, Q.; Sun Y. A novel benzo[d] imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome. Biochem. Pharmacol. 2013, 85, 1504-1512.

[26] Du, Z.Y.; Wei, X.; Huang, M.T.; Zheng, X.; Liu, Y.; Conney, A.; Zhang, K. Anti-proliferative, anti-inflammatory and antioxidant effects of curcumin analogue A2. Arch. Pharm. Res. 2013, 36, 1204-1210.

[27] Maydt, D.; De Spirt, S.; Muschelknautz, C.; Stahl, W.; Müller, T.J.J. Chemical reactivity and biological activity of chalcones and other α,β-unsaturated carbonyl compounds. Xenobiotica. 2013, 43, 711-718.

[28] Ou, J.L.; Mizushina, Y.; Wang, S.Y.; Chuang, D.Y.; Nadar, M.; Hsu, W.L. Structure-activity relationship analysis of curcumin analogues on anti-influenza virus activity. FEBS J. 2013, 280, 5829-5840.

[29] Chanda, D.; Bhushan, S.; Guru, S.K.; Shanker, K.; Wani, Z.; Rah, B.; Luqman, S.; Mondhe, D.M.; Pal, A.; Negi, A.S. Anticancer activity, toxicity and pharmacokinetic profile of an indanone derivative. Eur. J. Pharm. Sci. 2012, 47, 988-995.

[30] Li, C.S.; Black, W.C.; Chan, C.C.; Ford-Hutchinson, A.W.; Gauthier, J.Y.; Gordon, R.; Guay, D.; Kargman, S.; Lau, C.K. Cyclooxygenase-2 Inhibitors. Synthesis and Pharmacological Activities of 5-Methanesulfonamido-1-indanone Derivatives. J. Med. Chem. 1995, 38, 4897-4905.

[31] Patel, A.; Giles, D.; Basavarajaswamy, G.; Sreedhar, C.; Patel, A. Synthesis, pharmacological evaluation and molecular docking studies of indanone derivatives. Med. Chem. Res. 2012, 21, 4403-4411.

[32] Wiesenberg-Boettcher, I.; Schweizer, A.; Green, J.; Seltenmeyer, Y.; Müller, K. The pharmacological profile of CGP 28238, a highly potent anti-inflammatory compound. Inflamm. Res. 1989, 26, 240-242.

[33] Shrestha, A.; Oh, H.J.; Kim, M.J.; Pun, M.T.; Magar, T.B.T.; Bist, G.; Choi, H.; Park, P.H.; Lee, E.S. Design, synthesis, and structure-activity relationship study of halogen containing 2-benzylidene-1-indanone derivatives for inhibition of LPS-stimulated ROS production in RAW 264.7 macrophages. Eur. J. Med. Chem. 2017, 133, 121-138.

[34] Hiroe, H.; Yoshinori, N.; Takayuki, M.; Naoki, O.; Yasuharu, W.; Koichi, T.; Hiroaki, H.; Atsushi, M.; Kiyoshi, T. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J. Leukocyte Biol. 2014, 96, 1087-1100.

[35] Bukhari, S.N.A.; Lauro, G.; Jantan, I.; Bifulco, G.; Amjad, M.W. Pharmacological evaluation and docking studies of α,β-unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A2, cyclooxygenases, lipoxygenase and proinflammatory cytokines. Bioorg. Med. Chem. 2014, 22, 4151-4161.

[36] Zhu, S.; Moore, T.W.; Lin, X.; Morii, N.; Mancini, A.; Howard, R.B.; Culver, D.; Arrendale, R.F.; Reddy, P.; Evers, T.J.; Zhang, H.; Sica, G.; Chen, Z.G.; Sun, A.; Fu, H.; Khuri, F.R.; Shin, D.M.; Snyder, J.P.; Shoji, M. Synthetic curcumin analog EF31 inhibits the growth of head and neck squamous cell carcinoma xenografts. Integr. Biol. 2012, 4, 633-640.

[37] Downs, L.E.; Wolfe, D.M.; Schreiner, P.R. Organic Base-Mediated Condensation of Pyridinecarboxaldehydes to Azachalcones. Adv. Synth. Catal. 2005, 347, 235-238.

[38] Bauernfeind, F.G.; Horvath, G.; Stutz, A.; Alnemri, E.S.; MacDonald, K.; Speert, D.; Fernandes-Alnemri, T.; Wu, J.; Monks, B.G.; Fitzgerald, K.A.; Hornung, V.; Latz, E. Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression. J. Immunol. 2009, 183, 787-791.

[39] Pelegrin, P.; Surprenant, A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J. 2006, 25, 5071-5082.

[40] Mariathasan, S.; Weiss, D.S.; Newton, K.; McBride, J.; O’Rourke, K.; Roose-Girma, M.; Lee, W.P.; Weinrauch, Y.; Monaks, D.M.; Dixit, V.M. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006, 440, 228-232.
[41] Monteleone, M.; Stow, J. L.; Schroder, K. Evaluation of endothelial biomarkers as predictors of organ failures in septic shock patients. Cytokine. 2015, 74, 213-218.

作用于炎症小体的α,β-不饱和酮类化合物的合成及活性评价

Synthesis and biological evaluation of α,β-unsaturated carbonyl compounds targeting the NLRP3 inflammasome

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