Substituent effect on the preferred DNA binding mode and affinity of a homologous series of naphthalene diimides.

A combination of isothermal titration calorimetry (ITC), topoisomerase I DNA unwinding assays, and ethidium bromide displacement studies were employed to investigate the binding of a homologous series of naphthalene diimides (NDI) to DNA. Our results suggest that the nature of the substituent plays a significant role in both the preferred binding mode and relative binding affinity of the compounds of this study. Only intercalative-type binding (K=15±3×10(6)M(-1)) was observed for the NDI with the smallest substituent (trimethyl-ethylamino), while larger members of the series (diethylmethyl-, dipropylmethyl- and dibutylmethyl-ethylamino substituents) adopted an additional binding mode of higher affinity (K(1)=31-78×10(6)M(-1)).

Substituent control of DNA binding modes in a series of chalcogenoxanthylium photosensitizers as determined by isothermal titration calorimetry and topoisomerase I DNA unwinding assay.

The DNA binding efficacy and preferred mode of binding of a series of rhodamine-related chalcogenoxanthylium dyes was investigated by isothermal titration calorimetry (ITC) using ctDNA, [poly(dCdG)](2) and [poly(dAdT)](2), and by a topoisomerase I DNA unwinding (Topo I) assay. The dyes of this study showed tight binding to ctDNA with binding constants, K(b), on the order of 10(6)-10(7)M(-1). The ITC and Topo I assay studies suggested that the 9-substituent has a strong impact on binding modes ranging from an apparent preference for intercalation with a 9-2-thienyl substituent (similar binding to [poly(dCdG)](2) and [poly(dAdT)](2), re-supercoiling of DNA in the Topo I assay at <10(-5)M dye), to mixed binding modes with 9-phenyl derivatives (2- to 3-fold preference for binding to [poly(dAdT)](2), re-supercoiling of DNA in the Topo I assay at approximately 2 x 10(-5)M dye), to minor groove binding in a 9-(2-thienyl-5-diethylcarboxamide) derivative (strong preference for binding to [poly(dAdT)](2), did not show complete re-supercoiling in the Topo I assay). No binding to ctDNA was observed in one derivative with a 9-(3-thienyl-2-diethylcarboxamide) substituent, which cannot be co-planar with the xanthylium core. In series of dyes where the chalcogen atom was varied, the selenoxanthylium derivatives had 2- to 3-fold higher values of K(b) than the corresponding xanthylium, thioxanthylium, or telluroxanthylium derivatives, which all showed comparable values of K(b). The chalcogen atom appeared to have little influence on binding mode.