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Stereoselective synthesis of allele-specific BET inhibitors
Authors:
Adam G.
Bond
(University of Dundee)
,
Andrea
Testa
(University of Dundee)
,
Alessio
Ciulli
(University of Dundee)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Organic & Biomolecular Chemistry
, VOL 2
State:
Published (Approved)
Published:
August 2020
Diamond Proposal Number(s):
19844

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.
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I24-Microfocus Macromolecular Crystallography
Documents:
d0ob01165g.pdf