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

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).

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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Contributors

Author: Keith R. Fox

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