Stereoselective synthesis of allele-specific BET inhibitors
Autor: | Adam G. Bond, Alessio Ciulli, Andrea Testa |
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Rok vydání: | 2020 |
Předmět: |
BRD4
0303 health sciences Chemistry Organic Chemistry Nuclear Proteins Isothermal titration calorimetry Alkylation 010402 general chemistry 01 natural sciences Biochemistry Combinatorial chemistry 0104 chemical sciences Bromodomain Chiral column chromatography BET inhibitor 03 medical and health sciences chemistry.chemical_compound Enantiopure drug Stereoselectivity Physical and Theoretical Chemistry Derivative (chemistry) 030304 developmental biology |
Zdroj: | Organicbiomolecular chemistry. 18(38) |
ISSN: | 1477-0539 |
Popis: | Developing stereoselective synthetic routes that are efficient and cost-effective is important to allow easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) bromodomain 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 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 confirmed 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 inhibitor and a viable route that will facilitate wider access to this compound class. |
Databáze: | OpenAIRE |
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