DNA binding thermodynamics and sequence specificity of chiral piperazinecarbonyloxyalkyl derivatives of anthracene and pyrene

In this paper we report the DNA binding proper ties of piperazinecarbonyloxy-2-propyl derivatives of anthracene (2), pyrene (3), and phenylanthracene (4). An intercalative binding mode is found for 2 and 3, while the phenyl group of 4 prevents intercalation and leads to external binding. Preferential binding of the (S)-enantiomers is found for both anthracene 2 and pyrene 3. However, the enantiomeric preference is small, with K-(R)/K-(S) being around 0.5 for both the anthracene and the pyrene compounds. This is interpreted in terms of orientation polarity in the binding, by which any intrinsic enantioselectivity is canceled by averaging of opposite binding orientations. The affinities for poly(dA-dT)(2) (AT) are 10(4) M-1 for anthracene derivative 2, and 5 x 10(5) M-1 for pyrene derivative 2. The affinities for poly(dG-dC)(2) (GC) are I order of magnitude lower than those for AT. This is explained by steric interference of the piperazinium tail with the exocyclic amino groups of guanine in the minor groove of GC, leading to a more shallow intercalation in GC than in AT, as also indicated by significantly less negative reduced linear dichroism of the intercalator absorption bands in the GC complexes. This behavior is consistent with that observed for the previously studied achiral analogues.(1) Binding thermodynamics support the difference in binding mode between AT and GC. The binding enthalpy of the AT complexes is significantly more negative than that of the corresponding GC complexes. This indicates a larger overlap of intercalating moiety and nucleobases in the AT complexes, consistent with the linear dichroism results