Discovery and structure-activity relationship of 2-phenyl-oxazole-4-carboxamide derivatives as potent apoptosis inducers

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 17, 2006, Pages 4554-4558

  Tai, Vincent W F ^a   Sperandio, David ^a   Shelton, Emma J ^a   Litvak, Joane ^a   Pararajasingham, Keith ^a   Cebon, Ben ^a   Lohman, Julia ^a   Eksterowicz, John ^a   Kantak, Seema ^a   Sabbatini, Peter ^a   Brown, Cindy ^a   Zeitz, Jennifer ^a   Reed, Chris ^a   Maske, Bill ^a   Graupe, Doris ^a   Estevez, Alberto ^a   Oeh, Jason ^a   Wong, Darren ^a   Ni, Yong ^a   Sprengeler, Paul ^a   Yee, Robert ^a   Magill, Catherine ^a   Neri, Anthony ^a   Cai, Sui Xiong ^b   Drewe, John ^b   Qiu, Ling ^b   Herich, John ^b   Tseng, Ben ^b   Kasibhatla, Shailaja ^b   Spencer, Jeffrey R ^a   more..

^a CELERA   (United States)

^b EpiCept Corporation   (United States)

Author keywords

Antitumor; Apoptosis; Apoptosis activators; Oxazole

Indexed keywords

2 PHENYLOXAZOLE 4 CARBOXAMIDE; AMIDE; ANTINEOPLASTIC AGENT; DNA; OXAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER CELL CULTURE; CANCER GROWTH; CANCER INHIBITION; CANCER MODEL; CELL STRAIN; COLORECTAL CANCER; CONTROLLED STUDY; DRUG DESIGN; DRUG DETERMINATION; DRUG DNA BINDING; DRUG POTENCY; DRUG RECEPTOR BINDING; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; THERAPY EFFECT; TREATMENT OUTCOME; TREATMENT RESPONSE; XENOGRAFT;

AMIDES; ANIMALS; APOPTOSIS; CELL LINE, TUMOR; FEMALE; HUMANS; MICE; MOLECULAR STRUCTURE; OXAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 33746233282     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.06.018     Document Type: Article

References (18)

1. Lowe S.W., and Lin A.W. Carcinogenesis 21 (2000) 485
2. Reed J.C., and Tomaselli K.J. Curr. Opin. Biotechnol. 11 (2000) 586
3. Earnshaw W.C., Martins L.M., and Kaufmann S.H. Annu. Rev. Biochem. 68 (1999) 383
4. Arends M.J., and Wyllie A.H. Int. Rev. Exp. Pathol. 32 (1991) 223
5. Rich T., Allen R.L., and Wyllie A.H. Nature 407 (2000) 777
6. Zhang H.-Z., Drewe J., Tseng B., Kasibhatla S., and Cai S.X. Bioorg. Med. Chem 12 (2004) 3649
7. Zhang H.-Z., Kasibhatla S., Wang Y., Herich J., Huastella J., Tseng B., Drewe J., and Cai S.X. Bioorg. Med. Chem. 12 (2004) 309
8. Zhang H.-Z., Kasibhatla S., Kuemmerle J., Kemnitzer W., Ollis-Mason K., Qiu L., Crogan-Grundy C., Tseng B., Drewe J., and Cai S.X. J. Med. Chem. 48 (2005) 5215
9. Zhang H.-Z., Kasibhatla S., Guastella J., Tseng B., Drewe J., and Cai S.X. Bioconjugate Chem. 14 (2003) 458
10. 50 calculations:. Cai S.X., Nguyen B., Jia S., Herich J., Guastella J., Reddy S., Tseng B., Drewe J., and Kasibhatla S. J. Med. Chem. 46 (2003) 2474
11. 6) δ 1.51-1.68 (m, 6H), 3.55 (s, 2H), 3.58 (br s, 2H), 3.82 (br s, 2H), 4.35 (d, 2H, J = 5.6 Hz), 7.29 (br d, 2H, J = 8 Hz), 7.35-7.44 (m, 4H), 7.91 (dd, 2H, J = 1.6, 8.4 Hz), 8.56 (d, 1H, J = 2.4 Hz), 8.68 (t, 1H, J = 5.6 Hz); MS (ES) m/z 488.1 (MH+); MS calcd: 487.2 (M).
12. Wipf P., and Miller C.P. Tetrahedron Lett. 33 (1992) 907
13. Williams D.R., Lowder P.D., Gu Y.-G., and Brooks D.A. Tetrahedron Lett. 38 (1997) 331
14. Philips A.J., Uto Y., Wipf P., Reno M.J., and Williams D.R. Org. Lett. 2 (2000) 1165
15. MOE, Molecular Operating Environment; 2005.06; Chemical Computing Group, Inc., Montreal, Canada, 2005.
16. 6 cells per 10-cm dish and 24 h later were treated with compound 1k (1 μM) or vinblastine (400 nM) (final concentration of DMSO was 0.2%). After 48 h, cells were harvested and whole-cell lysates prepared using standard procedures. Cell extract (30 μg) was electrophoretically separated on a 4-20% Tris-glycine gel (Novex), blotted, and hybridized overnight with anti-PARP polyclonal antibody (cell signaling, Inc.). After subsequent washing and hybridization with HRP-anti-rabbit secondary antibody, proteins were detected using enhanced chemiluminescence according to the manufacturer's instructions.
17. 6 cells per 10-cm dish and 24 h later were treated with compound 1k (1 μM) or vinblastine (400 nM). After 48 h, the cells were harvested by trypsinization, washed with PBS (pH 7.4), and lysed in Triton X buffer (0.2% Triton X-100, 10 mM Tris, and 10 mM EDTA). After 10 min incubation on ice, lysates were pelleted and supernatant extracted twice with phenol/chloroform using standard procedures. Small MW DNA was then precipitated with 300 mM NaCl and ethanol at -80 °C. Precipitates were then lyophilized, resuspended in Tris/EDTA containing 0.6 mg/mL RNASe, and incubated at 37 °C for 30 min. Samples were then electrophoresed on a 2% TAE gel containing ethidium bromide and visualized under ultraviolet light.
18. 3, the mice were randomized into treatment groups and treated with compound 1k. All animals were weighted daily, and caliper measurements were taken three times a week after tumors were calculated by the Mann-Whitney rank sum test using SigmaStat software. Two-sided p-values are given at a 95% confidence level.