Identification of substituted pyrimido[5,4-b]indoles as selective toll-like receptor 4 ligands

Journal of Medicinal Chemistry

Volumn 56, Issue 11, 2013, Pages 4206-4223

  Chan, Michael ^a   Hayashi, Tomoko ^a   Mathewson, Richard D ^a   Nour, Afshin ^a   Hayashi, Yuki ^a   Yao, Shiyin ^a   Tawatao, Rommel I ^a   Crain, Brian ^a   Tsigelny, Igor F ^b   Kouznetsova, Valentina L ^a,b   Messer, Karen ^a   Pu, Minya ^a   Corr, Maripat ^c   Carson, Dennis A ^a   Cottam, Howard B ^a  

^a UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [(3 CYCLOHEXYL 4 OXO 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2YL)THIO]ACETIC ACID; 2 [(4 OXO 3 PHENETHYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2YL)THIO]ACETIC ACID; 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO] N (THIAZOL 2 YL)ACETAMIDE; 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO] N PENTYLACETAMIDE; 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETIC ACID; 2 [[3 (NAPHTHALEN 2 YL) 4 OXO 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 Y)]THIO]ACETIC ACID; 3 (NAPHTHALEN 1 YL) 2 THIOXO 2,3 DIHYDRO 1H PYRIMIDO[5,4 B]INDOL 4(5H) ONE; 3 CYCLOHEXYL 2 THIOXO 2,3 DIHYDRO 1H PYRIMIDO[5,4 B]INDOL 3 4(5H) ONE; 3 PHENETHYL 2 THIOXO 2,3 DIHYDRO 1H PYRIMIDO[5,4 B]INDOL 4(5H) ONE; 3 PHENYL 2 THIOXO 2,3 DIHYDRO 1H PYRIMIDO[5,4 B]INDOL 4(5H) ONE; ETHYL 2 [(2 CYANOPHENYL)AMINO]ACETATE; ETHYL 3 (3 BENZYLTHIOUREIDO) 1H INDOLE 2 CARBOXYLATE; ETHYL 3 (3 CYCLOHEXYLTHIOUREIDO) 1H INDOLE 2 CARBOXYLATE; ETHYL 3 (3 PHENYLTHIOUREIDO) 1H INDOLE 2 CARBOXYLATE; ETHYL 3 [3 (NAPHTHALEN 1 YL)THIOUREIDO] 1H INDOLE 2 CARBOXYLATE; ETHYL 3 AMINO 1H INDOLE 2 CARBOXYLATE; IMMUNOSTIMULATING AGENT; INDOLE DERIVATIVE; N (1H INDAZOL 6 YL) 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; N (NAPHTHALEN 2 YL) 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; N BUTYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; N CYCLOBUTYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL-2-YL)THIO]ACETAMIDE; N CYCLOHEPTYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; N CYCLOHEXYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4B]INDOL 2 YL)THIO]ACETAMIDE; N CYCLOOCTYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; N CYCLOPENTYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; N ETHYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; N HEXYL 2 [(4 OXO 3 PHENYL 4,5 DIHYDRO 3H PYRIMIDO[5,4 B]INDOL 2 YL)THIO]ACETAMIDE; TOLL LIKE RECEPTOR 4; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL CELL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DENDRITIC CELL; DRUG CYTOTOXICITY; DRUG IDENTIFICATION; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IMMUNOCOMPETENT CELL; INNATE IMMUNITY; MACROPHAGE; MOLECULAR DOCKING; MOLECULAR WEIGHT; MONONUCLEAR CELL; NONHUMAN; SPLEEN CELL;

ANIMALS; CELLS, CULTURED; CHEMOKINE CXCL10; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; IMMUNITY, INNATE; INDOLES; INTERLEUKIN-6; INTERLEUKIN-8; LIGANDS; LIPOPOLYSACCHARIDES; LYMPHOCYTE ANTIGEN 96; MICE; MICE, INBRED C57BL; MODELS, MOLECULAR; NF-KAPPA B; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; TOLL-LIKE RECEPTOR 4;

EID: 84879045041     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301694x     Document Type: Article

References (39)

1. Dev, A.; Iyer, S.; Razani, B.; Cheng, G. NF-κB and innate immunity Curr. Top. Microbiol. Immunol. 2011, 349, 115-143
2. Li, Q.; Verma, I. M. NF-κB regulation in the immune system Nature Rev. Immunol. 2002, 2, 725-734
3. Fang, H.; Wu, Y.; Huang, X.; Wang, W.; Bing, A. Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response J. Biol. Chem. 2011, 286, 30393-30400
4. Hemmi, H.; Takeuchi, O.; Kawai, T.; Kaisho, T.; Sato, S. A Toll-like receptor recognizes bacterial DNA Nature 2000, 408, 740-745 (Pubitemid 32015992)
5. Prins, R. M.; Craft, N.; Bruhn, K. W.; Khan-Farooqi, H.; Koya, R. C. The TLR-7 Agonist, Imiquimod, Enhances Dendritic Cell Survival and Promotes Tumor Antigen-Specific T Cell Priming: Relation to Central Nervous System Antitumor Immunity J. Immunol. 2005, 176, 157-164 (Pubitemid 43023259)
6. Lee, J.; Chuang, T.-H.; Redecke, V.; She, L.; Pitha, P. M. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of toll-like receptor 7 Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 6646-6651 (Pubitemid 36666635)
7. Lee, J.; Wu, C. C. N.; Lee, K. J.; Chuang, T.-H.; Katakura, K. Activation of anti-hepatitis C virus responses via Toll-like receptor 7 Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 1828-1833 (Pubitemid 43228778)
8. Smits, E. L. J. M.; Cools, N.; Lion, E.; Camp, K.; Ponsaerts, P. The Toll-like receptor 7/8 agonist resiquimod greatly increases the immunostimulatory capacity of human acute myeloid leukemia cells Cancer Immunol. Immunother. 2010, 59, 35-46
9. Coffman, R. L.; Sher, A.; Seder, R. A. Vaccine Adjuvants: Putting Innate Immunity to Work Immunity 2010, 33, 492-503
10. Mata-Haro, V.; Cekic, C.; Martin, M.; Chilton, P. M.; Casella, C. R. The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-Biased Agonist of TLR4 Science 2007, 316, 1628-1632 (Pubitemid 46982038)
11. Pu, M.; Hayashi, T.; Cottam, H.; Mulvaney, J.; Arkin, M. Analysis of high-throughput screening assays using cluster enrichment Stat. Med. 2012, 31, 4175-4189
12. Coats, S. R.; Pham, T.-T. T.; Bainbridge, B. W.; Reife, R. A.; Darveau, R. P. MD-2 Mediates the Ability of Tetra-Acylated and Penta-Acylated Lipopolysaccharides to Antagonize Escherichia coli Lipopolysaccharide at the TLR4 Signaling Complex J. Immunol. 2005, 175, 4490-4498 (Pubitemid 41361986)
13. Jiang, Z.; Georgel, P.; Du, X.; Shamel, L.; Sovath, S. CD14 is required for MyD88-independent LPS signaling Nature Immunol. 2005, 6, 565-570 (Pubitemid 41710726)
14. Wright, S. D.; Ramos, R. A.; Tobias, P. S.; Ulevitch, R. J.; Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein Science 1990, 249, 1431-1433
15. Nagai, Y.; Akashi, S.; Nagafuku, M.; Ogata, M.; Iwakura, Y. Essential role of MD-2 in LPS responsiveness and TLR4 distribution Nature Immunol. 2002, 3, 667-672 (Pubitemid 34752476)
16. Devani, M. B.; Shishoo, C. J.; Pathak, U. S.; Parikh, S. H.; Shah, G. F. Synthesis of 3-substituted thieno[2,3- d ]pyrimidin-4(3 H)-one-2-mercaptoacetic acids and their ethyl esters for pharmacological screening J. Pharm. Sci. 1976, 65, 660-664
17. Thurkauf, A.; Hutchison, A. Preparation of aryl heterocyclyl pyrimidines as GABA brain receptor ligands. (Neurogen Corp.) Cont. of U.S. Ser. No. 865,129, abandoned, 1994; 17 pp.
18. Monge, A.; Palop, J. A.; Recalde, I.; Martinez-Crespo, F.; Fernandez-Alvarez, E. Synthesis of 5 H -pyrimido[5,4- b ]indole derivatives and related compounds An. Quim., Ser. C: Quim. Org. Bioquim. 1985, 81, 267-270
19. Kawai, T.; Takeuchi, O.; Fujita, T.; Inoue, J.-I.; Muhlradt, P. F. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes J. Immunol. 2001, 167, 5887-5894 (Pubitemid 33062783)
20. 2 pomoter in the Toll-like receptor signaling J. Immunol. 2002, 169, 6668-6672 (Pubitemid 36899248)
21. Ohto, U.; Fukase, K.; Miyake, K.; Shimizu, T. Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2 Proc. Natl. Acad. Sci. U. S. A. 2012, 109, S7421-S7426
22. Meng, J.; Drolet, J. R.; Monks, B. G.; Golenbock, D. T. MD-2 Residues Tyrosine 42, Arginine 69, Aspartic Acid 122, and Leucine 125 Provide Species Specificity for Lipid IVA J. Biol. Chem. 2010, 285, 27935-27943
23. Vasl, J.; Oblak, A.; Gioannini, T. L.; Weiss, J. P.; Jerala, R. Novel Roles of Lysines 122, 125, and 58 in Functional Differences between Human and Murine MD-2 J. Immunol. 2009, 183, 5138-5145
24. Muroi, M.; Tanamoto, K.-i. Structural Regions of MD-2 That Determine the Agonist-Antagonist Activity of Lipid IVa J. Biol. Chem. 2006, 281, 5484-5491 (Pubitemid 43847643)
25. Saitoh, S.-i.; Akashi, S.; Yamada, T.; Tanimura, N.; Kobayashi, M. Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization Int. Immunol. 2004, 16, 961-969 (Pubitemid 38960874)
26. Walsh, C.; Gangloff, M.; Monie, T.; Smyth, T.; Wei, B. Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa J. Immunol. 2008, 181, 1245-1254
27. Shimazu, R.; Akashi, S.; Ogata, H.; Nagai, Y.; Fukudome, K. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4 J. Exp. Med. 1999, 189, 1777-1782 (Pubitemid 29272694)
28. Medzhitov, R.; Preston-Hurlburt, P.; Janeway, C. A., Jr. A human homolog of the Drosophila Toll protein signals activation of adaptive immunity Natur 1997, 388, 394-396
29. Park, B. S.; Song, D. H.; Kim, H. M.; Choi, B.-S.; Lee, H. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex Nature 2009, 458, 1191-1195
30. Macindoe, G.; Mavridis, L.; Venkatraman, V.; Devignes, M.-D.; Ritchie, D. W. HexServer: an FFT-based protein docking server powered by graphics processors Nucleic Acids Res. 2010, 38, W445-W449
31. Dewar, M. J. S. AMPAC: a general program for chemical calculations using procedures developed by the Dewar group Mod. Tech. Comput. Chem.: MOTECC-91 1991, 455-467
32. Hutchinson, M. R.; Loram, L. C.; Zhang, Y.; Shridhar, M.; Rezvani, N. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity Neuroscience 2010, 168, 551-563
33. Zimmer, S. M.; Liu, J.; Clayton, J. L.; Stephens, D. S.; Snyder, J. P. Paclitaxel Binding to Human and Murine MD-2 J. Biol. Chem. 2008, 283, 27916-27926
34. Hutchinson, M. R.; Zhang, Y.; Shridhar, M.; Evans, J. H.; Buchanan, M. M. Evidence that opioids may have toll-like receptor 4 and MD-2 effects Brain, Behav., Immun. 2009, 24, 83-95
35. Liu, L.; Ghosh, N.; Slivka, P. F.; Fiorini, Z.; Hutchinson, M. R. An MD2 Hot-Spot-Mimicking Peptide that Suppresses TLR4-Mediated Inflammatory Response in Vitro and in Vivo ChemBioChem 2011, 12, 1827-1831
36. Wu, C. C.; Hayashi, T.; Takabayashi, K.; Sabet, M.; Smee, D. F. Immunotherapeutic activity of a conjugate of a Toll-like receptor 7 ligand Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 3990-3995 (Pubitemid 47181566)
37. Chan, M.; Hayashi, T.; Kuy, C. S.; Gray, C. S.; Wu, C. C. Synthesis and immunological characterization of toll-like receptor 7 agonistic conjugates Bioconjugate Chem 2009, 20, 1194-1200
38. Hayashi, T.; Rao, S. P.; Takabayashi, K.; Van Uden, J. H.; Kornbluth, R. S. Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase Infect. Immun. 2001, 69, 6156-6164 (Pubitemid 32885177)
39. Crozat, K.; Georgel, P.; Rutschmann, S.; Mann, N.; Du, X. Analysis of the MCMV resistome by ENU mutagenesis Mamm. Genome 2006, 17, 398-406 (Pubitemid 44011965)