A substituent constant analysis of the interaction of substituted naphthalene monoimides with DNA

Article abstract of DOI:10.1021/jm00378a026

In a continuing analysis of substituent effects in intercalator-DNA interactions, an unsubstituted naphthalene monoimide, 1, with a 3-(dimethylamino)propyl group on the imide nitrogen has been prepared along with 3- and 4-nitro- (2 and 3) and 3- and 4-amino- (4 and 5) substituted derivatives. These derivatives allow an evaluation of the importance of the Hammett substituent constant and of the substituent position on the binding of naphthelene monoimides to DNA. Viscosity and spectrophotomeric analyses indicate that all five compounds bind to DNA by intercalation. The 4-nitro compound gives a smaller viscosity increase and binds only approximately one-third as strongly as the 3-nitro derivatives. It is postulated that this difference is due to significant angle that the 4-nitro group makes with the intercalated monoimide ring system. The 3-NO₂ group can assume a coplanar configuration with the monoimide ring system, allowing more favorable interactions with DNA base pairs, larger viscosity increases, and stronger binding to DNA. The binding constants of the 3-substutited monoimides are in the order 2 > 4 > 1 and, thus, do not follow a substituent constant pattern. The T(m) values from thermal melting of DNA, on the other hand, are in the oder 2 > 1 > 4, suggesting that the enthalpy contributions are significantly different for the binding of the three compounds to DNA. van't Hoff plots support this finding and indicate that both enthalpy and entropy contribute significantly to the binding free energy of 1 and 2 while the binding of 4 is primarily an enthalpic process. Plots of T(m) and 65°C log K values as a function of substituent constant for 1, 2, and 4 are linear. CPK model building studies suggest that 4 can form a hydrogen bond with the 5' diester oxygen of the sugar-phosphate backbone of DNA in an intercalation complex. This would lead to more favorable energetics of binding but a loss of mobility and/or available binding configurations with a resulting enthalpy-entropy compensation in the binding free energy of 4. This series of compounds dramatically illustrates the steric and hydrogen bonding complexity that can arise in attempts to design drugs to favorably interact with a DNA intercalation site as a potential bioreceptor.