Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure-Activity Relationship Study

Journal of Medicinal Chemistry

Volumn 58, Issue 14, 2015, Pages 5419-5436

  Xu, Li Li ^a   Zhu, Jun Feng ^a   Xu, Xiao Li ^a   Zhu, Jie ^a   Li, Li, ^a   Xi, Mei Yang ^a   Jiang, Zheng Yu ^a   Zhang, Ming Ye ^a   Liu, Fang ^a   Lu, Meng Chen ^a   Bao, Qi Chao ^a   Li, Qi ^a   Zhang, Chao ^a   Wei, Jin Lian ^a   Zhang, Xiao Jin ^a   Zhang, Lian Shan ^b   You, Qi Dong ^a,b   Sun, Hao Peng ^a  

^a CHINA PHARMACEUTICAL UNIVERSITY   (China)

^b Jiangsu Hengrui Medicine Co Ltd   (China)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 OXADIAZOLE DERIVATIVE; 3 (1H BENZO[D]IMIDAZOL 6 YL) 5 (4 FLUOROPHENYL) 1,2,4 OXADIAZOLE; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; DEXAMETHASONE; ENZYME; LIPOPOLYSACCHARIDE; NRF2 ACTIVATOR; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; OXADIAZOLE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHEMICAL STRUCTURE; CONTROLLED STUDY; DRUG SCREENING; DRUG SYNTHESIS; ENVIRONMENTAL STRESS; ENZYME INDUCTION; GENE EXPRESSION REGULATION; HCT116 CELL LINE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LUCIFERASE ASSAY; MOUSE; NONHUMAN; PHYSICAL CHEMISTRY; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; STRUCTURE ACTIVITY RELATION; ANIMAL; ANTIOXIDANT RESPONSIVE ELEMENT; C57BL MOUSE; CHEMISTRY; DRUG DESIGN; DRUG EFFECTS; FEMALE; GENETICS; METABOLISM; UPREGULATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTIOXIDANT RESPONSE ELEMENTS; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; FEMALE; HCT116 CELLS; HUMANS; MICE; MICE, INBRED C57BL; NF-E2-RELATED FACTOR 2; OXADIAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP; UP-REGULATION;

EID: 84937712953     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b00170     Document Type: Article

References (26)

1. Jaramillo, M. C.; Zhang, D. D. The emerging role of the Nrf2-Keap1 signaling pathway in cancer Genes Dev. 2013, 27, 2179-2191 10.1101/gad.225680.113
2. DeNicola, G. M.; Karreth, F. A.; Humpton, T. J.; Gopinathan, A.; Wei, C.; Frese, K.; Mangal, D.; Yu, K. H.; Yeo, C. J.; Calhoun, E. S.; Scrimieri, F.; Winter, J. M.; Hruban, R. H.; Iacobuzio-Donahue, C.; Kern, S. E.; Blair, I. A.; Tuveson, D. A. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis Nature 2011, 475, 106-109 10.1038/nature10189
3. Limonciel, A.; Jennings, P. A review of the evidence that ochratoxin A is an Nrf2 inhibitor: implications for nephrotoxicity and renal carcinogenicity Toxins 2014, 6, 371-379 10.3390/toxins6010371
4. Lau, A.; Tian, W.; Whitman, S. A.; Zhang, D. D. The predicted molecular weight of Nrf2: it is what it is not Antioxid. Redox Signaling 2013, 18, 91-93 10.1089/ars.2012.4754
5. Wilson, A. J.; Kerns, J. K.; Callahan, J. F.; Moody, C. J. Keap calm, and carry on covalently J. Med. Chem. 2013, 56, 7463-7476 10.1021/jm400224q
6. Kensler, T. W.; Wakabayashi, N.; Biswal, S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway Annu. Rev. Pharmacol. Toxicol. 2007, 47, 89-116 10.1146/annurev.pharmtox.46.120604.141046
7. Suzuki, T.; Motohashi, H.; Yamamoto, M. Toward clinical application of the Keap1-Nrf2 pathway Trends Pharmacol. Sci. 2013, 34, 340-346 10.1016/j.tips.2013.04.005
8. Sporn, M. B.; Liby, K. T. NRF2 and cancer: the good, the bad and the importance of context Nat. Rev. Cancer 2012, 12, 564-571 10.1038/nrc3278
9. Oktem, F.; Yilmaz, H. R.; Ozguner, F.; Olgar, S.; Ayata, A.; Uzar, E.; Uz, E. Methotrexate-induced renal oxidative stress in rats: the role of a novel antioxidant caffeic acid phenethyl ester Toxicol. Ind. Health 2006, 22, 241-247 10.1191/0748233706th265oa
10. Schmidt, T. J.; Ak, M.; Mrowietz, U. Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-L-cysteine - preparation of S-substituted thiosuccinic acid esters Bioorg. Med. Chem. 2007, 15, 333-342 10.1016/j.bmc.2006.09.053
11. Kaidery, N. A.; Banerjee, R.; Yang, L.; Smirnova, N. A.; Hushpulian, D. M.; Liby, K. T.; Williams, C. R.; Yamamoto, M.; Kensler, T. W.; Ratan, R. R.; Sporn, M. B.; Beal, M. F.; Gazaryan, I. G.; Thomas, B. Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease Antioxid. Redox Signaling 2013, 18, 139-157 10.1089/ars.2011.4491
12. Takaya, K.; Suzuki, T.; Motohashi, H.; Onodera, K.; Satomi, S.; Kensler, T. W.; Yamamoto, M. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system Free Radical Biol. Med. 2012, 53, 817-827 10.1016/j.freeradbiomed.2012.06.023
13. Wu, J.; Li, Q.; Wang, X.; Yu, S.; Li, L.; Wu, X.; Chen, Y.; Zhao, J.; Zhao, Y. Neuroprotection by curcumin in ischemic brain injury involves the Akt/Nrf2 pathway PLoS One 2013, 8, e59843 10.1371/journal.pone.0059843
14. Zhang, C.; Su, Z. Y.; Khor, T. O.; Shu, L.; Kong, A. N. Sulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation Biochem. Pharmacol. 2013, 85, 1398-1404 10.1016/j.bcp.2013.02.010
15. Kumar, V.; Kumar, v; Hassan, M.; Wu, H.; Thimmulappa, R. K.; Kumar, A.; Sharma, S. K.; Parmar, V. S.; Biswal, S.; Malhotra, S. V. Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells J. Med. Chem. 2011, 54, 4147-4159 10.1021/jm2002348
16. Hao, E.; Lang, F.; Chen, Y.; Zhang, H.; Cong, X.; Shen, X.; Su, G. Resveratrol alleviates endotoxin-induced myocardial toxicity via the Nrf2 transcription factor PLoS One 2013, 8, e69452 10.1371/journal.pone.0069452
17. Kim, H.; Kim, W.; Yum, S.; Hong, S.; Oh, J. E.; Lee, J. W.; Kwak, M. K.; Park, E. J.; Na, D. H.; Jung, Y. Caffeic acid phenethyl ester activation of Nrf2 pathway is enhanced under oxidative state: structural analysis and potential as a pathologically targeted therapeutic agent in treatment of colonic inflammation Free Radical Biol. Med. 2013, 65, 552-562 10.1016/j.freeradbiomed.2013.07.015
18. Steel, R.; Cowan, J.; Payerne, v.; O'Connell, M. A.; Searcey, M. Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction ACS Med. Chem. Lett. 2012, 3, 407-410 10.1021/ml300041g
19. Marcotte, D.; Zeng, W.; Hus, J. C.; McKenzie, A.; Hession, C.; Jin, P.; Bergeron, C.; Lugovskoy, A.; Enyedy, I.; Cuervo, H.; Wang, D.; Atmanene, C.; Roecklin, D.; Vecchi, M.; Vivat, V.; Kraemer, J.; Winkler, D.; Hong, V.; Chao, J.; Lukashev, M.; Silvian, L. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism Bioorg. Med. Chem. 2013, 21, 4011-4019 10.1016/j.bmc.2013.04.019
20. Hu, L.; Magesh, S.; Chen, L.; Wang, L.; Lewis, T. A.; Chen, Y.; Khodier, C.; Inoyama, D.; Beamer, L. J.; Emge, T. J.; Shen, J.; Kerrigan, J. E.; Kong, A. N.; Dandapani, S.; Palmer, M.; Schreiber, S. L.; Munoz, B. Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction Bioorg. Med. Chem. Lett. 2013, 23, 3039-3043 10.1016/j.bmcl.2013.03.013
21. Xi, M. Y.; Jia, J. M.; Sun, H. P.; Sun, Z. Y.; Jiang, J. W.; Wang, Y. J.; Zhang, M. Y.; Zhu, J. F.; Xu, L. L.; Jiang, Z. Y.; Xue, X.; Ye, M.; Yang, X.; Gao, Y.; Tao, L.; Guo, X. K.; Xu, X. L.; Guo, Q. L.; Zhang, X. J.; Hu, R.; You, Q. D. 3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as potent Nrf2/ARE inducers in human cancer cells and AOM-DSS treated mice J. Med. Chem. 2013, 56, 7925-7938 10.1021/jm400944k
22. Jiang, Z. Y.; Lu, M. C.; Xu, L. L.; Yang, T. T.; Xi, M. Y.; Xu, X. L.; Guo, X. K.; Zhang, X. J.; You, Q. D.; Sun, H. P. Discovery of Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitor Based on Molecular Binding Determinants Analysis J. Med. Chem. 2014, 57, 2736-2745 10.1021/jm5000529
23. Inoyama, D.; Chen, Y.; Huang, X.; Beamer, L. J.; Kong, A. N.; Hu, L. Optimization of fluorescently labeled Nrf2 peptide probes and the development of a fluorescence polarization assay for the discovery of inhibitors of Keap1-Nrf2 interaction J. Biomol. Screening 2012, 17, 435-447 10.1177/1087057111430124
24. Avdeef, A.; Bucher, J. J. Accurate measurements of the concentration of hydrogen ions with a glass electrode: Calibrations using the Prideaux and other universal buffer solutions and a computer-controlled automatic titrator Anal. Chem. 1978, 50, 2137-2142 10.1021/ac50036a045
25. Baell, J. B.; Holloway, G. A. New substructure filters for removal of Pan Assay Interference Compounds (PAINS) from screening libraries and for their exclusion in bioassays J. Med. Chem. 2010, 53, 2719-2740 10.1021/jm901137j
26. Auletta, J. J.; Alabran, J. L.; Kim, B. G.; Meyer, C. J.; Letterio, J. J. The Synthetic Triterpenoid, CDDO-Me, Modulates the Proinfl ammatory Response to In Vivo Lipopolysaccharide Challenge J. Interferon Cytokine Res. 2010, 30, 497-508 10.1089/jir.2009.0100