作为拓扑异构酶 II 毒物的安吖啶：药物-DNA 相互作用的重要性,Biochemistry

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作为拓扑异构酶 II 毒物的安吖啶：药物-DNA 相互作用的重要性
Biochemistry ( IF 2.9 ) Pub Date : 2012-02-10 00:00:00 , DOI: 10.1021/bi201159b
Adam C Ketron ₁ , William A Denny , David E Graves , Neil Osheroff

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Amsacrine ( m -AMSA) 是一种抗癌剂，对难治性急性白血病以及霍奇金和非霍奇金淋巴瘤具有活性。所述药物包括耦合到4'-氨基methanesulfon-的插层吖啶基部分的米-anisidide首基。m- AMSA 具有历史意义，因为它是第一种被证明具有拓扑异构酶 II 毒物作用的药物。尽管m- AMSA 被设计为 DNA 结合剂，但嵌入能力似乎并不是药物活性的唯一决定因素。因此，为了更全面地分析结构-功能关系以及 DNA 结合在m作用中的作用-AMSA，我们分析了一系列衍生物增强由人拓扑异构酶 IIα 和拓扑异构酶 IIβ 介导的 DNA 切割和嵌入 DNA 的能力。结果表明，3'-甲氧基（m - AMSA）对药物功能有积极影响，可能是通过限制头部向有利方向旋转。将甲氧基移至 2'-位（o - AMSA），这会取消药物功能，似乎会增加头基的旋转自由度，并可能损害三元内头基的 1'-取代基或其他部分的相互作用复杂的。最后，非插入式m-AMSA 头部基团在与吖啶部分分离时增强了酶介导的 DNA 切割，尽管亲和力降低了 100 倍。总之，我们的结果表明m- AMSA 作为拓扑异构酶 II 毒物的大部分活性和特异性体现在头基中，而 DNA 嵌入主要用于增加m- AMSA 对拓扑异构酶 II-DNA 切割复合物的亲和力.

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Amsacrine as a Topoisomerase II Poison: Importance of Drug–DNA Interactions

Amsacrine (m-AMSA) is an anticancer agent that displays activity against refractory acute leukemias as well as Hodgkin’s and non-Hodgkin’s lymphomas. The drug is comprised of an intercalative acridine moiety coupled to a 4′-amino-methanesulfon-m-anisidide headgroup. m-AMSA is historically significant in that it was the first drug demonstrated to function as a topoisomerase II poison. Although m-AMSA was designed as a DNA binding agent, the ability to intercalate does not appear to be the sole determinant of drug activity. Therefore, to more fully analyze structure–function relationships and the role of DNA binding in the action of m-AMSA, we analyzed a series of derivatives for the ability to enhance DNA cleavage mediated by human topoisomerase IIα and topoisomerase IIβ and to intercalate DNA. Results indicate that the 3′-methoxy (m-AMSA) positively affects drug function, potentially by restricting the rotation of the headgroup in a favorable orientation. Shifting the methoxy to the 2′-position (o-AMSA), which abrogates drug function, appears to increase the degree of rotational freedom of the headgroup and may impair interactions of the 1′-substituent or other portions of the headgroup within the ternary complex. Finally, the nonintercalative m-AMSA headgroup enhanced enzyme-mediated DNA cleavage when it was detached from the acridine moiety, albeit with 100-fold lower affinity. Taken together, our results suggest that much of the activity and specificity of m-AMSA as a topoisomerase II poison is embodied in the headgroup, while DNA intercalation is used primarily to increase the affinity of m-AMSA for the topoisomerase II–DNA cleavage complex.

更新日期：2012-02-10

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