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Use of aldehyde-alkyne-amine couplings to generate medicinal chemistry-relevant linkers

Use of aldehyde-alkyne-amine couplings to generate medicinal chemistry-relevant linkers
Use of aldehyde-alkyne-amine couplings to generate medicinal chemistry-relevant linkers

Copper catalyzed aldehyde-alkyne-amine (A3) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, a selection of linkers was purified by chiral HPLC to afford single enantiomers, the absolute configuration of which was determined by vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected linkers were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting chimeras), which degraded their target protein BRD4.

bromodomains, chiral separation, linkers, multicomponent reactions, PROTACs
1948-5875
278-284
McGown, Andrew
5809e935-f2bc-4222-8757-f8a07296bcb1
Vetma, Vesna
c1f7a330-3ebd-4056-ac0e-b091aacf5580
Crepin, Damien
f60154ec-4d29-451e-a8ee-6f9a6251747e
Lin, Yan
f3f15b46-e506-4e57-b35a-18daf97cdd8c
Adcock, Claire
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Craigon, Conner
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Nafie, Jordan
59e81e45-ddbc-424a-939d-1c8f24db82b9
von Emloh, Daniel
36760021-c585-483f-9211-93a1525bd77a
Sutton, Léa
cfdd9f64-9277-4b3b-a611-c6f5ec896bd6
Bailey, Kiera
23a7c731-0fc5-4e30-8b62-830115b32713
Edmunds, Lewis
fb59a904-93a3-4bf5-90a7-6fd80719cfc7
Sharma, Manvendra
9399d8ab-072e-4fb5-bbf8-54b916afb705
Wilden, Jonathan D.
fcfa61ce-75cd-4b4d-9c29-3c9695dd5742
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Tizzard, Graham J.
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Farnaby, William
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Ciulli, Alessio
6a734270-055b-47ed-b97d-51cff3fb50f1
Kostakis, George E.
dd72c724-c82e-4891-aa68-ccdb42cc6cb8
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
McGown, Andrew
5809e935-f2bc-4222-8757-f8a07296bcb1
Vetma, Vesna
c1f7a330-3ebd-4056-ac0e-b091aacf5580
Crepin, Damien
f60154ec-4d29-451e-a8ee-6f9a6251747e
Lin, Yan
f3f15b46-e506-4e57-b35a-18daf97cdd8c
Adcock, Claire
578b1ffe-2ab8-4587-94da-95aaa93b3853
Craigon, Conner
824bd7f4-1aee-46ec-9016-cd2338a6a1de
Nafie, Jordan
59e81e45-ddbc-424a-939d-1c8f24db82b9
von Emloh, Daniel
36760021-c585-483f-9211-93a1525bd77a
Sutton, Léa
cfdd9f64-9277-4b3b-a611-c6f5ec896bd6
Bailey, Kiera
23a7c731-0fc5-4e30-8b62-830115b32713
Edmunds, Lewis
fb59a904-93a3-4bf5-90a7-6fd80719cfc7
Sharma, Manvendra
9399d8ab-072e-4fb5-bbf8-54b916afb705
Wilden, Jonathan D.
fcfa61ce-75cd-4b4d-9c29-3c9695dd5742
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Farnaby, William
dc77f86a-9469-4cec-877c-3e5621268dab
Ciulli, Alessio
6a734270-055b-47ed-b97d-51cff3fb50f1
Kostakis, George E.
dd72c724-c82e-4891-aa68-ccdb42cc6cb8
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4

McGown, Andrew, Vetma, Vesna, Crepin, Damien, Lin, Yan, Adcock, Claire, Craigon, Conner, Nafie, Jordan, von Emloh, Daniel, Sutton, Léa, Bailey, Kiera, Edmunds, Lewis, Sharma, Manvendra, Wilden, Jonathan D., Coles, Simon J., Tizzard, Graham J., Farnaby, William, Ciulli, Alessio, Kostakis, George E. and Spencer, John (2025) Use of aldehyde-alkyne-amine couplings to generate medicinal chemistry-relevant linkers. ACS Medicinal Chemistry Letters, 16 (2), 278-284. (doi:10.1021/acsmedchemlett.4c00531).

Record type: Article

Abstract

Copper catalyzed aldehyde-alkyne-amine (A3) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, a selection of linkers was purified by chiral HPLC to afford single enantiomers, the absolute configuration of which was determined by vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected linkers were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting chimeras), which degraded their target protein BRD4.

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mcgown-et-al-2025-use-of-aldehyde-alkyne-amine-couplings-to-generate-medicinal-chemistry-relevant-linkers - Version of Record
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More information

Accepted/In Press date: 20 January 2025
e-pub ahead of print date: 25 January 2025
Published date: 13 February 2025
Keywords: bromodomains, chiral separation, linkers, multicomponent reactions, PROTACs
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Identifiers

Local EPrints ID: 498827
URI: http://eprints.soton.ac.uk/id/eprint/498827
DOI: doi:10.1021/acsmedchemlett.4c00531
ISSN: 1948-5875
PURE UUID: feb26553-3e6f-4306-80ac-68ed391a2c28
ORCID for Simon J. Coles: ORCID iD orcid.org/0000-0001-8414-9272
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779

Catalogue record

Date deposited: 03 Mar 2025 17:37
Last modified: 22 Aug 2025 01:48

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Contributors

Author: Andrew McGown
Author: Vesna Vetma
Author: Damien Crepin
Author: Yan Lin
Author: Claire Adcock
Author: Conner Craigon
Author: Jordan Nafie
Author: Daniel von Emloh
Author: Léa Sutton
Author: Kiera Bailey
Author: Lewis Edmunds
Author: Manvendra Sharma
Author: Jonathan D. Wilden
Author: Simon J. Coles ORCID iD
Author: Graham J. Tizzard ORCID iD
Author: William Farnaby
Author: Alessio Ciulli
Author: George E. Kostakis
Author: John Spencer

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