Wilson W D, Barton H J, Tanious F A, Kong S B, Strekowski L
Department of Chemistry, Georgia State University, Atlanta 30303.
Biophys Chem. 1990 Apr;35(2-3):227-43. doi: 10.1016/0301-4622(90)80011-u.
A number of unfused tricyclic aromatic intercalators have shown excellent activity as amplifiers of the anticancer activity of the bleomycins and the 4',6-diphenylpyrimidines, 2a and 2b, with terminal basic functions (4-methylpiperazino groups) have been synthesized to test the structural requirements for amplifier-DNA interactions. The terminal piperazine rings are bulky, have limited flexibility, and are twisted out of the phenyl ring plane in both 2a and 2b. With 2a the pyrimidine is unsubstituted at position 5 and the conformation predicted by molecular mechanics calculations has a 25-30 degrees twist between the phenyl and pyrimidine ring planes. With 2b the 5-position is substituted with a methyl group and this causes a larger twist angle (50-60 degrees) between the phenyl and pyrimidine planes. These conformational variations lead to markedly different DNA interactions for 2a and 2b. Absorption, CD and NMR spectral, viscometric, flow dichroism and kinetics results indicate that 2a binds strongly to DNA by intercalation while 2b binds more weakly in a groove complex. The general structure and conformation of 2a, a slightly twisted, unfused-aromatic system with terminal piperazino groups is more similar to groove-binding agents such as Hoechst 33258 than to intercalators. The fact that 2a forms a strong intercalation complex with DNA is unusual but in agreement with studies on other amplifiers of anticancer drug action. Molecular modeling studies provide a second unusual feature of the 2a intercalation complex. While most well-characterized intercalators bind with their bulky and/or cationic substitutents in the DNA minor groove, the cationic piperazino groups of 2a are too large to bind in the minor groove in an intercalation complex but can form strong interactions with DNA in the major groove. The tricyclic aromatic ring system of 2a stacks well with adjacent base-pairs in the major-groove complex and the piperazino groups have good electrostatic and van der Waals interactions with the DNA backbone.
许多未稠合的三环芳香族嵌入剂已显示出优异的活性，可作为博来霉素和4',6-二苯基嘧啶（2a和2b）抗癌活性的增强剂，已合成带有末端碱性官能团（4-甲基哌嗪基）的此类物质，以测试增强剂与DNA相互作用的结构要求。末端哌嗪环体积庞大，灵活性有限，在2a和2b中均扭曲出苯环平面。对于2a，嘧啶在5位未被取代，分子力学计算预测的构象在苯环和嘧啶环平面之间有25 - 30度的扭曲。对于2b，5位被甲基取代，这导致苯环和嘧啶平面之间的扭曲角更大（50 - 60度）。这些构象变化导致2a和2b与DNA的相互作用明显不同。吸收光谱、圆二色光谱和核磁共振光谱、粘度测定、流动二色性和动力学结果表明，2a通过嵌入作用与DNA强烈结合，而2b在沟槽复合物中的结合较弱。2a的一般结构和构象，即带有末端哌嗪基的略微扭曲的未稠合芳香体系，与沟槽结合剂如Hoechst 33258比与嵌入剂更相似。2a与DNA形成强嵌入复合物这一事实不同寻常，但与其他抗癌药物作用增强剂的研究结果一致。分子模拟研究揭示了2a嵌入复合物的另一个不同寻常的特征。虽然大多数特征明确的嵌入剂在DNA小沟中与它们的庞大和/或阳离子取代基结合，但2a的阳离子哌嗪基团太大，无法在嵌入复合物的小沟中结合，但可以在大沟中与DNA形成强相互作用。2a的三环芳香环系统在大沟复合物中与相邻碱基对很好地堆积，哌嗪基团与DNA主链有良好的静电和范德华相互作用。
