NUCLEIC-ACID INTERACTIONS OF UNFUSED AROMATIC CATIONS - EVALUATION OFPROPOSED MINOR-GROOVE, MAJOR-GROOVE, AND INTERCALATION BINDING MODES

Amidine derivatives of the 2,5-diphenylfuran aromatic system have acti vity against a variety of microorganisms. The compounds bind strongly to continuous sequences of AT base pairs in DNA, and there is general agreement that the compounds complex in the minor groove in AT sequenc es. Some of the derivatives also bind strongly in GC rich and mixed se quences of DNA, and both major-groove and intercalation binding modes have been suggested for this binding mode on the basis of different ex perimental observations. To obtain definitive information on the DNA b inding modes of these types of compounds, we have synthesized addition al derivatives, which were designed to provide improved distinction be tween major-groove and intercalation binding modes, and have extended the experimental analysis to include electric linear dichroism, high-r esolution NMR, and absorption, fluorescence, and CD spectroscopy resul ts. All of the spectral results as well as kinetics studies results su pport a minor-groove binding mode in AT sequences of DNA, as expected, while results with sequences containing GC or mixed AT and GC sequenc es support an intercalation mode for these compounds. The weak induced CD signals for the compounds in complex with poly d(G-C)(2), for exam ple, are characteristic of intercalation and the electric linear dichr oism spectra demonstrate clearly that the compounds have their transit ion dipoles oriented in the same plane as the DNA base pairs, exactly as predicted for intercalation binding. Chemical shift changes of the aromatic proton signals of the diphenylfuran ring system are all upfie ld by approximately 0.5 ppm or greater on complex formation with GC se quences, also as predicted for intercalation. The compounds have NOE c ontacts to DNA protons in both the major and the minor grooves, and th is is only possible if the compounds extend through the DNA double hel ix, as expected for an intercalation binding mode. Some of the discrep ancy in the literature may have arisen due to confusion caused by the mixed minor-groove and intercalation complexes of the diphenylfurans i n heterogeneous sequence DNA.