ml400323x_si_001.pdf (1.13 MB)
Thioester Bonds of Thiocoraline Can Be Replaced with NMe-Amide Bridges without Affecting Its DNA-Binding Properties
journal contribution
posted on 2014-01-09, 00:00 authored by Rubí Zamudio-Vázquez, Fernando Albericio, Judit Tulla-Puche, Keith R. FoxIn
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.