Denny W A, Wakelin L P
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Anticancer Drug Des. 1990 May;5(2):189-200.
The kinetics of association and dissociation of DNA complexes of the anti-tumour agents mitoxantrone, ametantrone and related 1,4-bis(alkylamino)anthraquinones have been determined by stopped-flow spectrophotometry, in order to study relationships between structure, kinetic parameters and biological activity. Variations in the structure of the side chains of ametantrone analogues had little effect on the kinetic stability of the complexes, but the mitoxantrone complexes dissociated about an order of magnitude more slowly, suggesting an important role for the two hydroxyl groups on the chromophore of the latter compound. The results are consistent with other n.m.r. and molecular mechanics data, which suggest a binding model where the chromophore intercalates perpendicularly to the DNA base pair axis. Dissociation studies with DNA homopolymers of varying base composition suggest the kinetic mechanism is a mixed parallel/sequential one, with the slowest dissociation processes being from GC-rich sites in both homopolymers and natural DNA. The results suggest guidelines for the design of more tumour-active analogues of the class.
为了研究结构、动力学参数和生物活性之间的关系，采用停流分光光度法测定了抗肿瘤药物米托蒽醌、氨甲蒽醌及相关的1,4 - 双（烷基氨基）蒽醌的DNA复合物的缔合和解离动力学。氨甲蒽醌类似物侧链结构的变化对复合物的动力学稳定性影响很小，但米托蒽醌复合物的解离速度要慢大约一个数量级，这表明后一种化合物发色团上的两个羟基起重要作用。这些结果与其他核磁共振和分子力学数据一致，这些数据表明存在一种结合模型，即发色团垂直于DNA碱基对轴插入。对不同碱基组成的DNA均聚物的解离研究表明，动力学机制是一种混合的平行/顺序机制，在均聚物和天然DNA中，最慢的解离过程都发生在富含GC的位点。这些结果为该类更具肿瘤活性的类似物的设计提供了指导方针。
