Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL

Edmonds, Anthony K, Oakes, Catherine S, Hassell-Hart, Storm, Bruyère, Didier, Tizzard, Graham J, Coles, Simon J, Felix, Robert, Maple, Hannah J, Marsh, Graham P and Spencer, John (2022) Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL. Organic and Biomolecular Chemistry. ISSN 1477-0520

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (629kB)

Abstract

ISOX-DUAL is a dual inhibitor of CBP/p300 (IC50 = 0.65 μM) and BRD4 (IC50 = 1.5 μM) bromodomains, and a useful chemical probe for epigenetic research. Aspects of the published synthetic route to this compound and its analogues are small-scale, poor-yielding or simply unamenable to scale-up without optimization. Herein we describe the development of a refined synthesis that circumvents the challenges of the original report, with notable improvements to several of the key synthetic transformations. Moreover, a general Suzuki Miyaura protocol for the late stage installation of alternative dimethyl-isoxazole acetyl-lysine (KAc) binding motifs is presented.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 05 May 2022 07:02
Last Modified: 05 May 2022 07:02
URI: http://sro.sussex.ac.uk/id/eprint/105654

View download statistics for this item

📧 Request an update