Targeting mismatched base pairs containing DNA using small molecules and their binding mechanism is a fundamental fact in the design of new types of drug molecules, and the use of these molecules as nucleic acid targeting therapeutics.1 In this report, we systematically delineate the binding mechanism of anticancer drug, Epirubicin Hydrochloride (EPR) with 20-mer duplex DNA having diverse Watson-Crick [cytosine(C)  guanine (G)/adenine (A) = thymine (T)] and non-Watson-Crick base pairs2 containing DNA, namely CA, CC, and CT mismatched DNA. The binding interactions have been monitored using steady-state fluorescence spectroscopy, Isothermal Titration Calorimetry (ITC) studies, and Fluorescence Correlation Spectroscopy (FCS) technique. From the thermal denaturation study, we observed that EPR can remarkably enhance the melting temperature (~17 C) of CC and CT mismatch DNA through intercalation binding mode. Binding constant values of the said interaction is maximum for CT/CC MM over the well matched DNA. The major challenge associated with the DNA targeting drug molecules is the removal of the excess drug (in the case of overdose) from the off-target site which is an important aspect of therapeutic applications.3 For this reason, besides deciphering the EPR-MM DNA interaction, furthermore in this work we have explored the sequestration of off-target bound EPR from DNA binding sites using a mixed micelle system made of a neutral tri-block copolymer (P123), and an anionic surfactant, sodium dodecyl sulfate (SDS).4 We discovered that the efficacy of drug sequestration is directly related to the binding affinity between DNA and EPR. This investigation may be valuable in the rational design of new mutated DNA targeting therapeutic agents and application of these molecules in disease diagnostic, and sensing.4

Exploring the Binding affinity of Epirubicin Hydrochloride towards Single Nucleotide Mismatched DNA and Subsequent Sequestration

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27th CRSI National Symposium in Chemistry

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