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Thiazole orange-carboplatin triplex-forming oligonucleotide (TFO) combination probes enhance targeted DNA crosslinking

Thiazole orange-carboplatin triplex-forming oligonucleotide (TFO) combination probes enhance targeted DNA crosslinking
Thiazole orange-carboplatin triplex-forming oligonucleotide (TFO) combination probes enhance targeted DNA crosslinking

We report a new class of carboplatin-TFO hybrid that incorporates a bifunctional alkyne-amine nucleobase monomer called AP-C3-dT that enables dual ‘click’ platinum(ii) drug conjugation and thiazole orange fluorophore coupling. Thiazole orange enhances the binding of Pt(ii)-TFO hybrids and provides an intrinsic method for monitoring triplex formation. These hybrid constructs possess increased stabilisation and crosslinking properties in comparison to earlier Pt(ii)-TFOs, and demonstrate sequence-specific binding at neutral pH.

2632-8682
Hennessy, Joseph
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Klimkowski, Piotr
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Singleton, Daniel
9be0cfc1-ca7a-4d93-810f-3fdc014d2c48
Gibney, Alex
29c6c360-f5ae-4c7b-8fb2-0507e634db30
Coche, Malou
6c3ad1dc-d6ea-4ef6-b2fe-94726ceec006
Farrell, Nicholas P.
beab2eff-2911-4c18-b867-ed991a972871
El-Sagheer, Afaf H.
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Brown, Tom
a2f3fa9b-3625-4c63-ad18-4ce65b85f3ee
Kellett, Andrew
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Hennessy, Joseph
c6c4ac5c-7c3b-4992-9247-f67f7b388a01
Klimkowski, Piotr
19202fc2-2dbd-4486-b01b-e0a6574b3586
Singleton, Daniel
9be0cfc1-ca7a-4d93-810f-3fdc014d2c48
Gibney, Alex
29c6c360-f5ae-4c7b-8fb2-0507e634db30
Coche, Malou
6c3ad1dc-d6ea-4ef6-b2fe-94726ceec006
Farrell, Nicholas P.
beab2eff-2911-4c18-b867-ed991a972871
El-Sagheer, Afaf H.
05b8295a-64ad-4fdf-ad57-c34934a46c04
Brown, Tom
a2f3fa9b-3625-4c63-ad18-4ce65b85f3ee
Kellett, Andrew
1de5738f-a91a-410c-96b6-c6b016b4a1c2

Hennessy, Joseph, Klimkowski, Piotr, Singleton, Daniel, Gibney, Alex, Coche, Malou, Farrell, Nicholas P., El-Sagheer, Afaf H., Brown, Tom and Kellett, Andrew (2023) Thiazole orange-carboplatin triplex-forming oligonucleotide (TFO) combination probes enhance targeted DNA crosslinking. RSC Medicinal Chemistry. (doi:10.1039/d3md00548h).

Record type: Article

Abstract

We report a new class of carboplatin-TFO hybrid that incorporates a bifunctional alkyne-amine nucleobase monomer called AP-C3-dT that enables dual ‘click’ platinum(ii) drug conjugation and thiazole orange fluorophore coupling. Thiazole orange enhances the binding of Pt(ii)-TFO hybrids and provides an intrinsic method for monitoring triplex formation. These hybrid constructs possess increased stabilisation and crosslinking properties in comparison to earlier Pt(ii)-TFOs, and demonstrate sequence-specific binding at neutral pH.

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Submitted date: 3 October 2023
Accepted/In Press date: 27 October 2023
e-pub ahead of print date: 31 October 2023
Additional Information: Funding Information: this project has received funding from the Irish Research Council (IRCLA/2022/3815), Science Foundation Ireland (12/RC/2275_P2), and the Novo Nordisk Foundation (NNF22OC0077099). We acknowledge funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 861381 (NATURE-ETN) and ClickGene (H2020-MSCA-ITN-2014-642023), and the Oxford University Medical and Life Sciences Translational Fund (MLSTF)—a consolidated fund comprising devolved funding from the MRC, Wellcome, and BBSRC. AHE-S acknowledges start-up funding from the University of Southampton.
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Identifiers

Local EPrints ID: 486017
URI: http://eprints.soton.ac.uk/id/eprint/486017
DOI: doi:10.1039/d3md00548h
ISSN: 2632-8682
PURE UUID: 82f8d35e-3ab1-493c-93ac-cb0cbe8b1fdb
ORCID for Afaf H. El-Sagheer: ORCID iD orcid.org/0000-0001-8706-1292

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Date deposited: 05 Jan 2024 17:53
Last modified: 18 Mar 2024 03:03

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Contributors

Author: Joseph Hennessy
Author: Piotr Klimkowski
Author: Daniel Singleton
Author: Alex Gibney
Author: Malou Coche
Author: Nicholas P. Farrell
Author: Afaf H. El-Sagheer ORCID iD
Author: Tom Brown
Author: Andrew Kellett

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