The University of Southampton
University of Southampton Institutional Repository

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
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.

1477-0520
4021-4029
Edmonds, Anthony K.
b3b4d718-cbd0-472a-9b7d-044c21f5bd60
Oakes, Catherine S.
ef0c51fc-f7f1-4c90-bf8b-6c85da4af284
Hassell-Hart, Storm
cb87c9ec-7c5c-4ba5-8893-1348694eb4bd
Bruyère, Didier
9bb6b60f-2af1-43b1-bb09-98075fe542d4
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Felix, Robert
acfd9272-cc4b-4838-bca1-8c31965d5a2e
Maple, Hannah J.
d25a19da-d87e-472f-b08f-ddc49354cd05
Marsh, Graham P.
937b77a4-3d88-43b7-9845-20ffb1804c62
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
Edmonds, Anthony K.
b3b4d718-cbd0-472a-9b7d-044c21f5bd60
Oakes, Catherine S.
ef0c51fc-f7f1-4c90-bf8b-6c85da4af284
Hassell-Hart, Storm
cb87c9ec-7c5c-4ba5-8893-1348694eb4bd
Bruyère, Didier
9bb6b60f-2af1-43b1-bb09-98075fe542d4
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Felix, Robert
acfd9272-cc4b-4838-bca1-8c31965d5a2e
Maple, Hannah J.
d25a19da-d87e-472f-b08f-ddc49354cd05
Marsh, Graham P.
937b77a4-3d88-43b7-9845-20ffb1804c62
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4

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), 4021-4029. (doi:10.1039/d2ob00609j).

Record type: Article

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 - Version of Record
Available under License Creative Commons Attribution.
Download (635kB)

More information

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
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779
ORCID for Simon J. Coles: ORCID iD orcid.org/0000-0001-8414-9272

Catalogue record

Date deposited: 16 Aug 2022 16:40
Last modified: 17 Aug 2022 01:37

Export record

Altmetrics

Contributors

Author: Anthony K. Edmonds
Author: Catherine S. Oakes
Author: Storm Hassell-Hart
Author: Didier Bruyère
Author: Simon J. Coles ORCID iD
Author: Robert Felix
Author: Hannah J. Maple
Author: Graham P. Marsh
Author: John Spencer

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×