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

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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

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