The G · C base‐pair preference of 2‐N‐methyl 9‐hydroxyellipticinium

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Abstract
Among the DNA‐intercalating drugs in the ellipticinium series, 9‐hydroxy derivatives elicit the highest antitumoral properties. In water these drugs display a very low fluorescence quantum yield. Replacement of H2O by D2O partially restores the fluorescence of the ellipticinium chromophore. The possibility that such a proton‐exchange mechanism could be involved in a base‐recognizing process at the DNA level (and therefore be responsible for some base preference) was examined by direct fluorescence titration in deuterated buffer and DNA/drug fluorescence energy transfer. These experimental approaches provide mutually consistent results showing that the 9‐hydroxylated drug recognizes specific DNA sites that are not recognized by the non‐hydroxylated drug.When compared to 2‐N‐methyl ellipticinium, the 2‐N‐methyl 9‐hydroxyellipticinium presents: (1) higher binding constants for each DNA studied; (2) a base dependence of the fluorescence properties of the bound form (fluorescence increment upon DNA binding varying over 5–11); (3) a base dependence of its DNA affinity constants (1.1–3.3 × 106 M−1) and of its site size (exclusion parameters varying over 3.0‐4.4); (4) a base dependence of its energy transfer from DNA bases.Analysis of the binding data suggests that the 9‐hydroxyl group of 2‐N‐methyl ellipticinium is responsible for a G · C base‐pair preference, the preferred binding site being a doublet sequence of two adjacent G · C which could be flanked either by a additional G · C base pair or by an A · T base pair.

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