Lown J W, Morgan A R, Yen S F, Wang Y H, Wilson W D
Biochemistry. 1985 Jul 16;24(15):4028-35. doi: 10.1021/bi00336a034.
The binding constants for interaction of the anticancer agents mitoxantrone and ametantrone and several congeners with calf thymus DNA and the effects of ionic strength changes have been determined spectrophotometrically. The agents show a preference for certain sequences, particularly those with GC base pairs, and the magnitude of the specificity depends on the specific substituents on the anthraquinone ring system. The binding constant for mitoxantrone with calf thymus DNA in 0.1 M Na+, pH 7, is approximately 6 X 10(6) M-1, and the rate constant for the sodium dodecyl sulfate driven dissociation of mitoxantrone from its calf thymus DNA complex under the same solution conditions and 20 degrees C was determined to be 1.3 s-1. The unwinding angle of mitoxantrone determined independently by viscosity measurements and by a novel assay employing calf thymus topoisomerase shows excellent agreement for a value of 17.5 degrees. The viscosity increase of sonicated calf thymus DNA varies considerably with the substituent on the anthraquinone ring system. Binding studies employing T4 and phi w-14 DNAs in which the major groove is occluded and the reverse experiment with anthramycin-treated calf thymus DNA indicate at least part of the mitoxantrone molecule may lie in the minor groove.
已通过分光光度法测定了抗癌药物米托蒽醌、氨茴环素及其几种同系物与小牛胸腺DNA相互作用的结合常数以及离子强度变化的影响。这些药物对某些序列有偏好，特别是那些含有GC碱基对的序列，特异性的程度取决于蒽醌环系统上的特定取代基。在0.1 M Na⁺、pH 7条件下，米托蒽醌与小牛胸腺DNA的结合常数约为6×10⁶ M⁻¹，在相同溶液条件和20℃下，十二烷基硫酸钠驱动米托蒽醌从小牛胸腺DNA复合物中解离的速率常数测定为1.3 s⁻¹。通过粘度测量和采用小牛胸腺拓扑异构酶的新方法独立测定的米托蒽醌解旋角，对于17.5°的值显示出极好的一致性。超声处理的小牛胸腺DNA的粘度增加随蒽醌环系统上的取代基有很大变化。使用T4和ϕw - 14 DNA（其中大沟被封闭）进行的结合研究以及用氨茴霉素处理小牛胸腺DNA的反向实验表明，米托蒽醌分子的至少一部分可能位于小沟中。
