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

  • Org Biomol Chem. 2022 May 18;20(19):4021-4029. doi: 10.1039/d2ob00609j.
Anthony K Edmonds  1 ,  Catherine S Oakes  2 ,  Storm Hassell-Hart  1 ,  Didier Bruyère  2 ,  Graham J Tizzard  3 ,  Simon J Coles  3 ,  Robert Felix  2 ,  Hannah J Maple  2 ,  Graham P Marsh  2 ,  John Spencer  1  4
Affiliations
  • 1. Chemistry Department, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QJ, UK. [email protected].
  • 2. Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Bristol, BS11 9QD, UK.
  • 3. National Crystallography Service, School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.
  • 4. Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QJ, UK.
PMID: 35506991 DOI: 10.1039/d2ob00609j
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.