De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho A P, Giuliani F C
Division of Experimental Oncology B, Istituto Nazionale Tumori, Milan, Italy.
Mol Pharmacol. 1995 Jul;48(1):30-8.
The cytotoxic activity of mitoxantrone and related anthracenediones has been ascribed to the ability of these compounds to interfere with DNA topoisomerase II function, resulting in DNA cleavage stimulation. The molecular details of enzyme inhibition by these intercalating agents remain to be defined. In an attempt to identify the structural determinants for optimal activity, the molecular and cellular effects of a series of heteroanalogues bearing different side-chains were examined in relation to the physico-chemical and DNA binding properties of these compounds. The results indicated that substitution of a pyridine ring for the dihydroxyphenylene ring in the planar chromophore caused a marked reduction of cytotoxic activity and of the ability to stimulate topoisomerase II-mediated DNA damage in intact cells and with simian virus 40 DNA in vitro. Although all tested derivatives were shown to intercalate into DNA, their DNA binding affinities were appreciably lower than that of mitoxantrone. The behavior of 2-aza derivatives more closely resembled that of ametantrone, suggesting that the potency of agents of this class is influenced more by the presence of hydroxyl groups than by the phenylene ring. The observation that a dramatic reduction (or loss) of the ability of aza derivatives to stimulate DNA cleavage is associated with a marked reduction of cytotoxic potency supports a primary role of topoisomerase II-mediated effects in the mechanism of action of the effective agents of this class. Because appreciable cytotoxic activity and significant in vivo antitumor efficacy are retained by compounds inactive (or poorly active) in inhibition of topoisomerase II, these results are consistent with multiple effects of anthracenediones at the cellular level.
米托蒽醌及相关蒽二酮的细胞毒性活性归因于这些化合物干扰DNA拓扑异构酶II功能的能力，从而导致DNA裂解刺激。这些嵌入剂对酶的抑制作用的分子细节仍有待确定。为了确定最佳活性的结构决定因素，研究了一系列带有不同侧链的杂类似物的分子和细胞效应，并将其与这些化合物的物理化学性质和DNA结合特性相关联。结果表明，在平面发色团中用吡啶环取代二羟基苯环会导致细胞毒性活性以及在完整细胞中刺激拓扑异构酶II介导的DNA损伤的能力和在体外对猿猴病毒40 DNA的刺激能力显著降低。尽管所有测试衍生物均显示可嵌入DNA，但其与DNA的结合亲和力明显低于米托蒽醌。2-氮杂衍生物的行为更类似于氨茴环素，这表明此类药物的效力受羟基存在的影响大于苯环。氮杂衍生物刺激DNA裂解的能力显著降低（或丧失）与细胞毒性效力显著降低相关，这一观察结果支持了拓扑异构酶II介导的效应在这类有效药物作用机制中的主要作用。由于在抑制拓扑异构酶II方面无活性（或活性较差）的化合物仍保留了相当的细胞毒性活性和显著的体内抗肿瘤功效，这些结果与蒽二酮在细胞水平上的多种作用一致。
