Bischoff G, Gromann U, Lindau S, Skölziger R, Witkowski W, Bohley C, Naumann S, Sági J, Meister W V, Hoffmann S
Martin Luther University Halle-Wittenberg, Department of Biochemistry, Saale, Germany.
J Biomol Struct Dyn. 2000 Oct;18(2):199-208. doi: 10.1080/07391102.2000.10506658.
Several 2.7-bis-[(dialkylamino)-acetylamino]-fluoren-9-one derivatives (fluoramides) were synthesized as analogues of the DNA binding compound tilorone (2,7-bis[(diethylamino)-ethoxy]-fluoren-9-one). Previous studies showed the drugs to induce cytokines and inhibit reverse transcription. Here, their binding to DNA was evaluated using UV and circular dichroism studies. Like tilorone, the fluoramides derivatives also intercalate resulting in increased Tm values and new CD signatures. A preference to alternating A-T and G-C sequences was detected; only minor interaction to homologous sequences was observed. Moreover, no upper limit in the drug/DNA ratio was found, testing limit being the precipitation of the drug. However, surface plasmon resonance (SPR) studies of tilorone and 2,7-bis-[(dipropylamino)-acetyl-amino]-fluoren-9-one, indicate an astonishing drug/base pair ratio (r > 1), which point to a multitude of interactions under SPR conditions. Molecular modeling calculations, where the geometries of the complexes optimized under the assumption of intercalative and multitude of suprahelical arrangements, rationalize the observations. Based on the thermodynamic and biological studies, a structure-function model is proposed.
合成了几种2.7 - 双[（二烷基氨基）- 乙酰氨基] - 芴 - 9 - 酮衍生物（氟酰胺）作为DNA结合化合物泰勒霉素（2,7 - 双[（二乙氨基） - 乙氧基] - 芴 - 9 - 酮）的类似物。先前的研究表明这些药物可诱导细胞因子并抑制逆转录。在此，使用紫外和圆二色性研究评估了它们与DNA的结合情况。与泰勒霉素一样，氟酰胺衍生物也会嵌入，导致熔解温度（Tm）值升高并产生新的圆二色性特征。检测到对交替的A - T和G - C序列有偏好；仅观察到与同源序列的轻微相互作用。此外，未发现药物/DNA比例的上限，测试极限是药物沉淀。然而，泰勒霉素和2,7 - 双[（二丙氨基） - 乙酰氨基] - 芴 - 9 - 酮的表面等离子体共振（SPR）研究表明存在惊人的药物/碱基对比率（r > 1），这表明在SPR条件下存在多种相互作用。分子建模计算在插入和多种超螺旋排列的假设下优化了复合物的几何结构，从而使这些观察结果合理化。基于热力学和生物学研究，提出了一个结构 - 功能模型。
