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New synthetic routes to triazolo-benzodiazepine analogues: expanding the scope of the bump-and-hole approach for selective bromo and extra-terminal (bet) bromodomain inhibition

New synthetic routes to triazolo-benzodiazepine analogues: expanding the scope of the bump-and-hole approach for selective bromo and extra-terminal (bet) bromodomain inhibition
New synthetic routes to triazolo-benzodiazepine analogues: expanding the scope of the bump-and-hole approach for selective bromo and extra-terminal (bet) bromodomain inhibition
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.
0022-2623
1492-1500
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Lin-Shiao, Enrique
cc4a9881-6e79-476e-a85b-13c4cb46c250
Zengerle, Michael
e413419c-1c98-4234-bec6-a5ba024f22f1
Tallant, Cynthia
989888e4-6d85-4f39-8748-17e4027495ea
Ciulli, Alessio
6a734270-055b-47ed-b97d-51cff3fb50f1
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Lin-Shiao, Enrique
cc4a9881-6e79-476e-a85b-13c4cb46c250
Zengerle, Michael
e413419c-1c98-4234-bec6-a5ba024f22f1
Tallant, Cynthia
989888e4-6d85-4f39-8748-17e4027495ea
Ciulli, Alessio
6a734270-055b-47ed-b97d-51cff3fb50f1

Baud, Matthias, Lin-Shiao, Enrique, Zengerle, Michael, Tallant, Cynthia and Ciulli, Alessio (2016) New synthetic routes to triazolo-benzodiazepine analogues: expanding the scope of the bump-and-hole approach for selective bromo and extra-terminal (bet) bromodomain inhibition. [in special issue: Epigenetics] Journal of Medicinal Chemistry, 59 (4), 1492-1500. (doi:10.1021/acs.jmedchem.5b01135).

Record type: Article

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.

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e-pub ahead of print date: 14 September 2015
Published date: 25 February 2016

Identifiers

Local EPrints ID: 400485
URI: https://eprints.soton.ac.uk/id/eprint/400485
ISSN: 0022-2623
PURE UUID: 854f8622-ecc8-467f-9e83-c4a283d84ca1
ORCID for Matthias Baud: ORCID iD orcid.org/0000-0003-3714-4350

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Date deposited: 16 Sep 2016 14:25
Last modified: 15 Aug 2019 00:31

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