Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα

Minniti, Elirosa; De Vivo, Marco; Osheroff, Neil; Rosini, Michela; Minarini, Anna; Riccardi, Laura; Sissi, Claudia; Byl, Jo Ann W.

doi:10.1016/j.bmcl.2017.09.011

Journal Article

FZJ-2017-08382

Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα

Minniti, E. ; Byl, J. A. W. ; Riccardi, L. ; Sissi, C. ; Rosini, M. ; De Vivo, M.FZJ* ; Minarini, A. (Corresponding author) ; Osheroff, N. (Corresponding author)

2017
Elsevier Science Amsterdam [u.a.]

Bioorganic & medicinal chemistry letters 27(20), 4687 - 4693 (2017) [10.1016/j.bmcl.2017.09.011]

This record in other databases:

Please use a persistent id in citations: doi:10.1016/j.bmcl.2017.09.011

Abstract: It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIα inhibitors. Although xanthone derivatives inhibit topoisomerase IIα-catalyzed ATP hydrolysis, mechanistic studies indicate that they do not act at the ATPase site. Rather, they appear to function by blocking the ability of DNA to stimulate ATP hydrolysis. On the basis of activity, competition, and modeling studies, we propose that xanthones interact with the DNA cleavage/ligation active site of topoisomerase IIα and inhibit the catalytic activity of the enzyme by interfering with the DNA strand passage step.

Classification: