Krueger W C, Duchamp D J, Li L H, Moscowitz A, Petzold G L, Prairie M D, Swenson D H
Chem Biol Interact. 1986 Jul-Aug;59(1):55-72. doi: 10.1016/s0009-2797(86)80055-2.
In this work, we report on the binding of the novel antitumor agent CC-1065 to poly(dA).poly(dT) and to mixtures of dA and dT oligomers as determined by electronic absorption and circular dichroism (CD) methods. In addition, the DNA binding properties of CC-1065 and its binding mechanism are compared to those of netropsin. CC-1065 binds to the polymer by at least three mechanisms to produce one irreversibly and two reversibly bound species. One reversibly bound species is moderately stable, but in time (days), it converts to the irreversibly bound species. Both of these species bind within the minor groove of the polymer and exhibit intense CC-1065 induced CD spectra. The other reversibly bound species does not acquire an induced CD. CC-1065 forces B-form duplex formation between mixtures of single strand dA and dT oligomers and binds irreversibly to the duplexes without showing the presence of an intermediate, reversibly bound species. The induced CD increases with increasing length of the oligomer, from the 5-mer (barely detectable CD) to the 14-mer (intense CD). The 7-, 10- and 14-mer mixtures bind about 1, between 1 and 2, and between 2 and 3 CC-1065 molecules, respectively. Computer graphic models of the CC-1065-DNA complex show that the covalent adduct of CC-1065 and unreacted CC-1065 can attain the same close van der Waals contacts between adenine C2 hydrogens and antibiotic CH groups that were observed in the crystal structure of the netropsin-DNA complex. These contacts may account for the dA-dT base pair binding specificity of CC-1065 and for the stability of the reversibly bound CC-1065 species.
在本研究中，我们报告了新型抗肿瘤药物CC - 1065与聚（dA）·聚（dT）以及dA和dT寡聚物混合物的结合情况，这是通过电子吸收光谱和圆二色性（CD）方法测定的。此外，还将CC - 1065的DNA结合特性及其结合机制与纺锤菌素进行了比较。CC - 1065通过至少三种机制与聚合物结合，产生一种不可逆结合的物种和两种可逆结合的物种。一种可逆结合的物种具有中等稳定性，但随着时间（数天）推移，它会转化为不可逆结合的物种。这两种物种都在聚合物的小沟内结合，并呈现出强烈的CC - 1065诱导CD光谱。另一种可逆结合的物种不会产生诱导CD。CC - 1065促使单链dA和dT寡聚物混合物之间形成B型双链体，并不可逆地与双链体结合，未显示出存在中间可逆结合物种的情况。诱导CD随着寡聚物长度的增加而增强，从5聚体（几乎检测不到CD）到14聚体（强烈的CD）。7聚体、10聚体和14聚体混合物分别结合约1个、1至2个和2至3个CC - 1065分子。CC - 1065 - DNA复合物的计算机图形模型表明，CC - 1065的共价加合物和未反应的CC - 1065在腺嘌呤C2氢原子和抗生素CH基团之间可以实现与纺锤菌素 - DNA复合物晶体结构中观察到的相同紧密范德华接触。这些接触可能解释了CC - 1065对dA - dT碱基对的结合特异性以及可逆结合的CC - 1065物种的稳定性。
