title: A substituent constant analysis of the interaction of substituted naphthalene monoimides with DNA.
abstract: In a continuing analysis of substituent effects in intercalator-DNA interactions, an unsubstituted naphthalene monoimide, with a 3-(dimethylamino)propyl group on the imide nitrogen has been prepared along with 3- and 4-nitro- and 3- and 4-amino-substituted derivatives. These derivatives allow an evaluation of the importance of the Hammett substituent constant and of the substituent position on the binding of naphthalene monoimides to DNA. Viscosity and spectrophotometric 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 derivative. It is postulated that this difference is due to the 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-substituted monoimides are in the order 2 greater than 4 greater than 1 and, thus, do not follow a substituent constant pattern. The Tm values from thermal melting of DNA, on the other hand, are in the order 2 greater than 1 greater than 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 Tm and 65 degrees 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.
mesh_terms: D000818:Animals; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D007094:Imides / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D007364:Intercalating Agents / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009691:Nucleic Acid Denaturation; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013950:Thymus Gland; D014783:Viscosity
chemical_list: D007094:Imides; D007202:Indicators and Reagents; D007364:Intercalating Agents; D009281:Naphthalenes; D004247:DNA