Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists.
Crystallographic analysis of ligands bound to HDM2 suggested that 7-substituted 1,4-diazepine-2,5-diones could mimic the alpha-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC(50) of 13 and 3.6 microM, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers.
Raboisson
Pierre
P
Department of Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA.
Marugán
Juan José
JJ
Schubert
Carsten
C
Koblish
Holly K
HK
Lu
Tianbao
T
Zhao
Shuyuan
S
Player
Mark R
MR
Maroney
Anna C
AC
Reed
Rolanda L
RL
Huebert
Norman D
ND
Lattanze
Jennifer
J
Parks
Daniel J
DJ
Cummings
Maxwell D
MD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D001381:Azepines; D008024:Ligands; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2