Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives as novel small molecule chaperone amplifiers

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4303-4307

  Zhou, Yuefen ^a   Wei, Linyi ^a   Brady, Thomas P ^a   Murali Mohan Redddy, P S ^a   Nguyen, Tram ^a   Chen, Jinhua ^a   Au, Qingyan ^a   Yoon, Il Sang ^a   Yip, Gary ^a   Zhang, Bin ^a   Barber, Jack R ^a   Ng, Shi Chung ^a  

^a CytRx Corporation   (United States)

Author keywords

Cytoprotection; Heat shock proteins (HSPs); HSF1; Neurodegenerative diseases; OGD; Protein misfolding; Pyrimidotriazinedione derivatives; Rotenone stress; Small molecule chaperone amplifiers; Stress granule

Indexed keywords

1 ETHYL 6 METHYL 3 (THIOPHEN 2 YL)PYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7(1H,6H) DIONE; 3 (2 YL)PYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7(1H,6H) DIONE; 5,7 DIOXO 3 (2 YL) 1,5,6,7 TETRAHYDROPYRIMIDO[5,4 E][1,2,4]TRIAZINE 4 OXIDE; 6 CHLORO PYRIMIDINE 2,4(1H,3H)DIONE; ARIMOCLOMOL; CELASTROL; CHAPERONE; HEAT SHOCK TRANSCRIPTION FACTOR 1; PYRIMIDINE DERIVATIVE; ROTENONE; UNCLASSIFIED DRUG;

ARTICLE; CELL PROTECTION; CELL VIABILITY; CONTROLLED STUDY; CYTOTOXICITY; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; GENE AMPLIFICATION; GENETIC TRANSCRIPTION; HEAT STRESS; HUMAN; HUMAN CELL; PROTON NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL LINE, TUMOR; CHEMISTRY, PHARMACEUTICAL; DNA-BINDING PROTEINS; DRUG DESIGN; GLUCOSE; HUMANS; MODELS, CHEMICAL; MOLECULAR CHAPERONES; NEURODEGENERATIVE DISEASES; OXYGEN; PROTEIN CONFORMATION; PROTEIN FOLDING; PYRIMIDINONES; RATS; ROTENONE; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTION FACTORS; TRIAZINES; URACIL;

HUMAN ECHOVIRUS 1;

EID: 67649934700     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.073     Document Type: Article

References (24)

1. Leigh P.N., Whitwell H., Garofalo O., Buller J., Swash M., Martin J.E., Gallo J.-M., Weller R.O., and Anderton B.H. Brain 114 (1991) 775
2. Agorogiannis E.I., Agorogiannis G.I., Papadimitriou A., and Hadjigeorgiou G.M. Neuropathol. Appl. Neurobiol. 30 (2004) 215
3. Muchowski P.J., and Wacker J.L. Nat. Rev. Neurosci. 6 (2005) 11
4. Walsh D.M., and Selkoe D.J. Protein Pept. Lett. 11 (2004) 213
5. Caughey B., and Lansbury P.T. Annu. Rev. Neurosci. 26 (2003) 267
6. Pirkkala L., Nykanen P., and Sistonen L. FASEB J. 15 (2001) 1118
7. Cotto J., Fox S., and Morimoto R.I. J. Cell Sci. 110 (1997) 2925
8. Au Q., Kanchanastit P., Barber J.R., Ng S.C., and Zhang B. J. Biomol. Screen 13 (2008) 953
9. Sõti C., Nagy E., Giricz Z., Vígh L., Csermely P., and Ferdinandy P. British J. Pharmacol. 146 (2005) 769
10. Boggs J. Bioworld Today 20 (2009) 1
11. Shamim M.T., Ukena D., Padgett W.L., and Daly J.W. J. Med. Chem. 32 (1989) 1231
12. Petry, S.; Barimghaus, K.-H.; Tennagels, N.; Mueller, G. U.S. Patent 2004/0242583 Al, 2004.
13. 4) and concentrated in vacuo. The residue was purified by automated flash chromatography (ISCO, CombiFlash Companion purchased from Teledyne ISCO) on silica gel (0-10% of MeOH in DCM) to give the desired products (2). The yields ranged from 44% to 95%. The synthesis was referred to the procedure as described in WO 2004/007499 A1 and WO04/065387.
14. 6, 400 MHz): δ 1.43 ppm (t, 3H, J = 5.72 Hz), 3.28 (s, 3H), 4.43 (q, 2H, J = 5.79), 7.26 (t, 1H, J = 3.06 Hz), 7.87 (d, 1H, J = 4.25 Hz), 7.88 (d, 1H, J = 2.47 Hz). The synthesis was referred to the procedure described in Lacrampe, J. F. A., et al. WO 2004/007498 A2, 2004.
15. 50 values and curve fitting were calculated using Prism 4.0 (GraphPad Software, San Diego, CA) with nonlinear regression analysis. A maximum percentage <20% HSF1 granule positive cells (compared to 7% in the DMSO negative control) was considered inactive.
16. Caboni P., Sherer T., Zhang N., Taylor G., Na H., Greenamyre J., and Casida J. Chem. Res. Toxicol. 17 (2004) 1540
17. 50 values and curve fitting were calculated using Prism 4.0 (GraphPad Software, San Diego, CA) with nonlinear regression analysis. Maximum percent cytoprotection <20% was considered inactive.
18. 50 values and curve fitting were calculated using Prism 4.0 (GraphPad Software, San Diego, CA) with nonlinear regression analysis.
19. Corson T.W., and Crews C.M. Cell 130 (2007) 769
20. Greenamyre J.T., Betarbet R., and Sherer T.B. Parkin. Relat. Disord. (2003) S59
21. Lim K.-L., et al. Human Mol. Gen. 14 (2005) 3885
22. Wang X., Qin Z.-H., Leng Y., Wang Y., Jin X., Chase T.N., and Bennett M.C. J. Neurochem. 83 (2002) 1094
23. Giffard R.G., Xu L., Zhao H., Carrico W., Ouyang Y., Qiao Y., Sapolsky R., Steinberg G., Hu B., and Yenari M.A. J. Exp. Biol. 207 (2004) 3213
24. DMSO × 100%.