Stereoselective synthesis of allele-specific BET inhibitors.
Org Biomol Chem
; 18(38): 7533-7539, 2020 10 07.
Article
in En
| MEDLINE
| ID: mdl-32756710
ABSTRACT
Developing stereoselective synthetic routes that are efficient and cost-effective allows easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) domain proteins, Brd2, Brd3, Brd4 and BrdT, required a wasteful, late-stage alkylation step and expensive chiral separation. To circumvent these limitations, we developed a route based on stereocontrolled alkylation of an N-Pf protected aspartic acid derivative that was used in a divergent, racemisation-free protocol to yield structurally diverse and enantiopure triazolodiazepines. With this approach, we synthesized bumped thienodiazepine-based BET inhibitor, ET-JQ1-OMe, in five steps and 99% ee without the need for chiral chromatography. Exquisite selectivity of ET-JQ1-OMe for Leu-Ala and Leu-Val mutants over wild-type bromodomain was established by isothermal titration calorimetry and X-ray crystallography. Our new approach provides unambiguous chemical evidence for the absolute stereochemistry of the active, allele-specific BET inhibitors and a viable route that will open wider access to this compound class.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Nuclear Proteins
Language:
En
Journal:
Org Biomol Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2020
Document type:
Article
Affiliation country:
United kingdom