Novel 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists with improved cellular activity

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 13, 2006, Pages 3463-3468

  Leonard, Kristi ^a   Marugan, Juan Jose ^a   Raboisson, Pierre ^a   Calvo, Raul ^a   Gushue, Joan M ^a   Koblish, Holly K ^a   Lattanze, Jennifer ^a   Zhao, Shuyuan ^a   Cummings, Maxwell D ^a   Player, Mark R ^a   Maroney, Anna C ^a   Lu, Tianbao ^a  

^a Development LLC   (United States)

Author keywords

Benzodiazepinedione; Hdm2; p53

Indexed keywords

1,4 BENZODIAZEPINE 2,5 DIONE DERIVATIVE; BENZODIAZEPINE DERIVATIVE; PROTEIN MDM2; PROTEIN P53; UNCLASSIFIED DRUG; MDM2 PROTEIN, HUMAN;

APOPTOSIS; ARTICLE; CELL ACTIVITY; CELL GROWTH; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; PROTEIN PROTEIN INTERACTION; CELL PROLIFERATION; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; DRUG SCREENING; HUMAN; METABOLISM; PROTEIN BINDING; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; SYNTHESIS; TUMOR CELL LINE;

APOPTOSIS; BENZODIAZEPINES; CELL LINE, TUMOR; CELL PROLIFERATION; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; MOLECULAR STRUCTURE; PROTEIN BINDING; PROTO-ONCOGENE PROTEINS C-MDM2; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR SUPPRESSOR PROTEIN P53;

EID: 33746627694     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.04.009     Document Type: Article

References (18)

1. Kubbutat M.H.G., and Vousden K.H. Mol. Med. Today 4 (1998) 250
2. Harris C.C. J. Natl. Cancer Int. 88 (1996) 1442
3. Vogelstein B., and Kinzler K.W. Cell 70 (1992) 523
4. Oren M. J. Biol. Chem. 274 (1999) 36031
5. Picksley S.M., and Lane D.P. Bioessays 15 (1993) 689
6. Piette J., Nell H., and Marechal V. Oncogene 15 (1995) 1001
7. Chene P. Nat. Rev. Cancer 3 (2003) 102
8. Bottger A., Bottger V., Sparks A., Liu W.L., Howard S.F., and Lane D.P. Curr. Biol. 7 (1997) 860
9. Blaydes J.P., Gire V., Rowson J.M., and Wynford-Thomas D. Oncogene 14 (1997) 1859
10. Wasylyk C., Salvi R., Argentini M., Dureuil C., Delumeau I., Abecassis J., Debussche L., and Wasylyk B. Oncogene 18 (1999) 1921
11. Zhao J., Wang M., Chen J., Luo A., Wang X., Wu M., Yin D., and Liu Z. Cancer Lett. 183 (2002) 69
12. Vassilev L.T., Vu B.T., Graves B., Carvajal D., Podlaski F., Filipovic Z., Kong N., Kammlott U., Lukacs C., Klein C., Fotouhi N.A., and Liu E.A. Science 303 (2004) 844
13. Grasberger B.L., Lu T., Schubert C., Parks D.J., Carver T.E., Koblish H.K., Cummings M.D., LaFrance L.V., Milkiewicz K.L., Calvo R.R., Maguire D., Lattanze J., Franks C.F., Zhao S., Ramachandren K., Bylebyl G.R., Zhang M., Manthey C.L., Petrella E.C., Pantoliano M.W., Deckman I.C., Spurlino J.C., Maroney A.C., Tomczuk B.E., Molloy C.J., and Bone R.F. J. Med. Chem. 48 (2005) 909
14. Parks D.J., LaFrance L.V., Calvo R.R., Milkiewicz K.L., Gupta V., Lattanze J., Ramachandren K., Carver T.E., Petrella E.C., Cummings M.D., Maguire D., Grasberger B.L., and Lu T. Bioorg. Med. Chem. Lett. 15 (2005) 765
15. Raboisson P., Marugan J.J., Schubert C., Koblish H.K., Lu T., Zhao S., Player M.R., Maroney A.C., Reed R.L., Huebert N.D., Lattanze J., Parks D.J., and Cummings M.D. Bioorg. Med. Chem. Lett. 15 (2005) 1857
16. The evaluation of the inhibitory activity of our compounds is based on the displacement of a peptide substrate attached in the N-terminus with fluorescein (FP assay).
17. In order to confirm that these compounds were stimulating p53 activity, we measured the induction of PIG-3 (p53 inducible gene 3). Polyak K., Xia Y., Zweier J.L., Kinzler K.W., and Vogelstein B. Nature 389 (1997) 300 JAR choriocarcinoma cells, which overexpress both Hdm2 and p53, were treated with various antagonists and cellular PIG-3 protein was measured by ELISA (Exalpha, Watertown, MA). Results greater than 100 ng PIG-3 normalized to total protein were considered positive for specific activation of p53.
18. Compound 28 was isolated as a byproduct of the reduction of the nitro functional group in the synthesis of compound 27.