Download MendeleyNew Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition.
Baud, M.G., Lin-Shiao, E., Zengerle, M., Tallant, C., Ciulli, A.(2016) J Med Chem 59: 1492-1500
- PubMed: 26367539
- DOI: https://doi.org/10.1021/acs.jmedchem.5b01135
- Primary Citation of Related Structures:
5DFB, 5DFC, 5DFD - PubMed Abstract:
We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains.
Organizational Affiliation:
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , James Black Centre, Dow Street, Dundee DD1 5EH, U.K.
