Stevenson K A, Yen S F, Yang N C, Boykin D W, Wilson W D
J Med Chem. 1984 Dec;27(12):1677-82. doi: 10.1021/jm00378a026.
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.
在对嵌入剂与DNA相互作用中取代基效应的持续分析中，已制备出一种在酰亚胺氮上带有3 -（二甲基氨基）丙基的未取代萘单酰亚胺，以及3 - 和4 - 硝基以及3 - 和4 - 氨基取代的衍生物。这些衍生物有助于评估哈米特取代基常数以及取代基位置对萘单酰亚胺与DNA结合的重要性。粘度和分光光度分析表明，所有这五种化合物均通过嵌入作用与DNA结合。4 - 硝基化合物导致的粘度增加较小，其结合强度仅约为3 - 硝基衍生物的三分之一。据推测，这种差异是由于4 - 硝基基团与嵌入的单酰亚胺环系统形成的显著角度所致。3 - NO₂基团可与单酰亚胺环系统呈共面构型，从而与DNA碱基对产生更有利的相互作用，使粘度增加更大，与DNA的结合更强。3 - 取代单酰亚胺的结合常数顺序为2大于4大于1，因此并不遵循取代基常数模式。另一方面，DNA热变性的Tm值顺序为2大于1大于4，这表明这三种化合物与DNA结合时的焓贡献有显著差异。范特霍夫图支持这一发现，并表明焓和熵对1和2的结合自由能都有显著贡献，而4的结合主要是一个焓驱动的过程。1、2和4的Tm值和65℃时的log K值与取代基常数的关系图呈线性。CPK模型构建研究表明，在嵌入复合物中，4可与DNA糖 - 磷酸主链的5' - 二酯氧形成氢键。这将导致更有利的结合能量学，但会损失流动性和/或可用的结合构型，从而在4的结合自由能中产生焓 - 熵补偿。这一系列化合物显著说明了在试图设计与作为潜在生物受体的DNA嵌入位点进行有利相互作用的药物时可能出现的空间和氢键复杂性。
