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Thioester bonds of Thiocoraline can be replaced with NMe-Amide bridges without affecting its DNA-binding properties

Thioester bonds of Thiocoraline can be replaced with NMe-Amide bridges without affecting its DNA-binding properties
Thioester bonds of Thiocoraline can be replaced with NMe-Amide bridges without affecting its DNA-binding properties
In the search for new drug candidates for DNA recognition, affinity and sequence selectivity are two of the most important features. NMe-azathiocoraline, a synthetic antitumor bisintercalator derived from the natural marine product thiocoraline, shows similar potency to the parent compound, as well as possessing enhanced stability. Analysis of the DNA-binding selectivity of NMe-azathiocoraline by DNase I footprinting using universal substrates with all 136 tetranucleotides and all possible symmetrical hexanucleotide sequences revealed that, although this ligand binds to all CpG steps with lower affinities than thiocoraline, it displays additional binding to AT-rich sites. Moreover, fluorescence melting studies showed a strong interaction of the synthetic molecule with CACGTG and weaker binding to ACATGT and AGATCT. These findings demonstrate that NMe-azathiocoraline has the same mode of action as thiocoraline, mimicking its DNA-binding selectivity despite the substitution of its thioester bonds by NMe-amide bridges.
1948-5875
45-50
Zamudio-Vázquez, Rubí
b14c0797-52a0-4ec3-9428-361a505c74cb
Albericio, Fernando
d2fa993a-fb9f-4871-b8e6-051f0828dffa
Tulla-Puche, Judit
60b81374-b2d3-4fd1-8a26-8682529a3dd0
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f
Zamudio-Vázquez, Rubí
b14c0797-52a0-4ec3-9428-361a505c74cb
Albericio, Fernando
d2fa993a-fb9f-4871-b8e6-051f0828dffa
Tulla-Puche, Judit
60b81374-b2d3-4fd1-8a26-8682529a3dd0
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f

Zamudio-Vázquez, Rubí, Albericio, Fernando, Tulla-Puche, Judit and Fox, Keith R. (2014) Thioester bonds of Thiocoraline can be replaced with NMe-Amide bridges without affecting its DNA-binding properties. ACS Medicinal Chemistry Letters, 5 (1), 45-50. (doi:10.1021/ml400323x).

Record type: Article

Abstract

In the search for new drug candidates for DNA recognition, affinity and sequence selectivity are two of the most important features. NMe-azathiocoraline, a synthetic antitumor bisintercalator derived from the natural marine product thiocoraline, shows similar potency to the parent compound, as well as possessing enhanced stability. Analysis of the DNA-binding selectivity of NMe-azathiocoraline by DNase I footprinting using universal substrates with all 136 tetranucleotides and all possible symmetrical hexanucleotide sequences revealed that, although this ligand binds to all CpG steps with lower affinities than thiocoraline, it displays additional binding to AT-rich sites. Moreover, fluorescence melting studies showed a strong interaction of the synthetic molecule with CACGTG and weaker binding to ACATGT and AGATCT. These findings demonstrate that NMe-azathiocoraline has the same mode of action as thiocoraline, mimicking its DNA-binding selectivity despite the substitution of its thioester bonds by NMe-amide bridges.

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More information

Published date: 2014
Organisations: Molecular and Cellular

Identifiers

Local EPrints ID: 363327
URI: http://eprints.soton.ac.uk/id/eprint/363327
ISSN: 1948-5875
PURE UUID: f82ce391-5e8a-4d7c-8dfa-189a8572259b
ORCID for Keith R. Fox: ORCID iD orcid.org/0000-0002-2925-7315

Catalogue record

Date deposited: 24 Mar 2014 13:38
Last modified: 15 Mar 2024 02:36

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Contributors

Author: Rubí Zamudio-Vázquez
Author: Fernando Albericio
Author: Judit Tulla-Puche
Author: Keith R. Fox ORCID iD

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