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

2012; American Chemical Society; Volume: 51; Issue: 8 Linguagem: Inglês

10.1021/bi201159b

1943-295X

Adam C. Ketron, William A. Denny, David E. Graves, Neil Osheroff,

Synthesis and pharmacology of benzodiazepine derivatives

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.