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

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posted on 2023-06-10, 03:20 authored by Anthony Edmonds, Catherine S Oakes, Storm Hassell-HartStorm Hassell-Hart, Didier Bruyère, Graham J Tizzard, Simon J Coles, Robert Felix, Hannah J Maple, Graham P Marsh, John SpencerJohn Spencer
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.

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Publication status

  • Published

File Version

  • Published version

Journal

Organic and Biomolecular Chemistry

ISSN

1477-0520

Publisher

Royal Society of Chemistry

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2022-05-05

First Open Access (FOA) Date

2022-05-05

First Compliant Deposit (FCD) Date

2022-05-04

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