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

作者：Ketron Adam C; Denny William A; Graves David E^*; Osheroff Neil

来源：Biochemistry, 2012, 51(8): 1730-1739.

DOI：10.1021/bi201159b

Amsacrine (m-AMSA) is an anticancer agent that displays activity against refractory acute leukemias as well as Hodgkin%26apos;s and non-Hodgkin%26apos;s lymphomas. The drug is comprised of an intercalative acridine moiety coupled to a 4%26apos;-amino-methane-sulfon-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 Ha and topoisomerase II beta and to intercalate DNA. Results indicate that the 3%26apos;-methoicy (m-AMSA) positively affects drug function, potentially by restricting the rotation of the headgroup in a favorable orientation. Shifting the methoxy to the 2%26apos;-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%26apos;-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.

• 出版日期2012-2-28