Different Binding Mode in AT and GC Sequences for Unfused-Aromatic Dications

Abstract

We have previously synthesized a 2,5-diphenylfuranamidine dication (4) and presented evidence that this compound binds to AT sequences in DNA by a minor-groove interaction mode but binds to GC sequences by intercalation (1,2). To probe these sequence-dependent binding modes in more detail, and particularly to obtain additional evidence for the binding mode in GC rich sequences, we have synthesized and studied the DNA complexes of 1-3 which have the furan ring of 4 replaced by 2,6-substituted pyridine (1), pyrimidine (2), or triazine (3) ring systems. The three compounds with a six-membered central ring system bind to AT DNA sequences more weakly than the furan compound, but retain the minor-groove binding mode. The pyridine and pyrimidine derivatives bind to GC sequences of DNA more strongly than the furan, but the triazine derivative binds more weakly. The aromatic proton signals of 1-3, as previously observed with 4 shift upfield by approximately 0.5 ppm or greater on complex formation with polyd(G-C)2. This and other spectroscopic as well as viscosity and kinetics results indicate that 1-4 bind to GC sites in DNA by intercalation. A nonclassical intercalation model, with the twisted-unfused, aromatic ring system intercalated into an intercalation site of matching structure can explain all of our and the literature results for the GC binding mode of these unfused, aromatic compounds.

Torsional Dynamics and Orientation of DNA−DAPI Complexes

“…We also studied whether the parameters of the system such as the torsional force constant and the angle of the transition dipole moment with respect to the helical axis can be considered independent of the P/D concentration. It is well established that several binding modalities are present in the DAPI/DNA complex and that, at very low P/D ratio, at least a second binding modality is occurring in which DAPI interacts with the phosphates Wilson et al, 1989;Tanious et al, 1994). Based on this consideration, a separate fit was attempted in which the value of the torsional constant and of the intrinsic anisotropy, r 0 , was allowed to vary between experiments (Table 2b).…”

“…Energy transfer between identical molecules do not affect the lifetime of the excited state if all molecules are spectroscopically equivalent, but it can affect the decay of the emission anisotropy. In the case of DAPI bound to DNA, there are at least two different binding modalities, one in which DAPI is bound to AT sites and gives a fluorescent species and a second modality of binding in which DAPI is interacting also with GC pairs and gives a nonfluorescent species (the quantum yield is a factor of about 50 less than the AT-bound species) (Manzini et al, 1983(Manzini et al, , 1985bWilson et al, 1989Wilson et al, , 1990Tanious et al, 1994). The GC-bound species is populated only at very low P/D ratios.…”

“…It is known that, in addition to binding to AT sites, DAPI can also bind to GC pairs, although with less affinity and without fluorescence enhancement. A number of recent studies have also shown that the fluorescence spectroscopic characteristics of DAPI depends on the DNA sequence (Wilson et al, 1990;Tanious et al, 1992Tanious et al, , 1994Eriksson et al, 1993).…”

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

“…In a related study, the nucleic acid binding properties of a series of 2,5-diphenylfuran dications were found to vary in interaction with DNA from AT selective minor-groove binding, to classical intercalation at GC sites, to threading intercalation at GC sites, depending upon the intrinsic nature of the cationic groups [3]. Recent reports [10,11] have suggested that 2,5-bis[(4-amidino)phenyl]furan also binds in the major groove of DNA in addition to binding in the minor groove, however this view has been questioned [12]. The crystal structure of a complex between 2,5-bis[(4-amidino)phenyl]furan and d(CGCGAATTCGCG) 2 was recently solved and clearly illustrates the minor-groove-binding mode [13].…”

4',6-Diamidino-2-phenylindole (DAPI) interacts with rare structures of GC polymers

“…In fact, a number of studies have shown that the¯uorescence characteristics of DAPI depend on DNA sequence and that DAPI can interact with GC sequences, although with less anity than to AT sequences. So far, the molecular mechanism responsible for the interaction between DAPI and GC sequences has not been properly clari®ed (Wilson et al 1990;Tanious et al 1992;Eriksson et al 1993;Kim et al 1993;Sehlstedt et al 1993;Tanious et al 1994;Colson et al 1995). Intercalation of the dye between GC or mixed AT/GC sites was originally proposed by Wilson et al (1989Wilson et al ( , 1990.…”