Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL
Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL
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.
4021-4029
Edmonds, Anthony K.
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Oakes, Catherine S.
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Hassell-Hart, Storm
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Bruyère, Didier
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Tizzard, Graham J.
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Coles, Simon J.
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Felix, Robert
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Maple, Hannah J.
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Marsh, Graham P.
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Spencer, John
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27 April 2022
Edmonds, Anthony K.
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Oakes, Catherine S.
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Hassell-Hart, Storm
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Bruyère, Didier
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Tizzard, Graham J.
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Coles, Simon J.
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Felix, Robert
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Maple, Hannah J.
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Marsh, Graham P.
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Spencer, John
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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, 20 (19), .
(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.
Text
d2ob00609j
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Accepted/In Press date: 25 April 2022
Published date: 27 April 2022
Additional Information:
Funding Information:
We are grateful for an EPSRC iCASE award (to AKE) from Bio-Techne (Tocris) and EPSRC as well as EPSRC funding (SHH; grant number: EP/P026990/1) and for the National Crystallography Service for structural studies.12
Publisher Copyright:
© 2022 The Royal Society of Chemistry
Identifiers
Local EPrints ID: 468482
URI: http://eprints.soton.ac.uk/id/eprint/468482
ISSN: 1477-0520
PURE UUID: b70061bc-c440-411e-ae7b-2599c4cd8e72
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Date deposited: 16 Aug 2022 16:40
Last modified: 18 Mar 2024 02:54
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Contributors
Author:
Anthony K. Edmonds
Author:
Catherine S. Oakes
Author:
Storm Hassell-Hart
Author:
Didier Bruyère
Author:
Robert Felix
Author:
Hannah J. Maple
Author:
Graham P. Marsh
Author:
John Spencer
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