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

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.

Study on Synthesis and Biological Evaluation of 3-Aryl Substituted Xanthone Derivatives as Novel and Potent Tyrosinase Inhibitors

“…18) In recent years, xanthone derivatives have been received considerable attention in the field of medicinal chemistry because of their diversely biological functions, 20,21) such as anti-oxidant, 22) anti-hypertensive, 23) anti-convulsant, 24) anti-cholinesterase, 25) anti-malarial, 26) antimicrobial, 27) anti-inflammatory, 28) and anti-cancer activities. 29) Besides, they also served as the effective inhibitors of several enzymes like α-glycosidase, 30,31) topoisomerase, 32) proteinkinase, 33) aromatase. 34) Driven by both the biologically applied powers and the favorable pharmacological properties, indeed, xanthone skeleton has been defined as one of the privileged structural motifs for next stage of certain new drug screening and discovery.…”

D-Ring-Modified Analogues of Luotonin A with Reduced Planarity: Design, Synthesis, and Evaluation of Their Topoisomerase Inhibition-Associated Cytotoxicity

“…Topoisomerase II is the target of a number of anticancer agents in clinical use, including etoposide, amsacrine, and doxorubicin [3, 11]. Other known topoisomerase II targeted anticancer frameworks include quercetin [12] and ellipticine and its derivatives and related heterocycles such as carbazoles [13–15], xanthone-polyamine conjugates [16], polyheterocyclic compounds with a tertiary amino side chain [17], nucleosides [18], and titanocenes [19]. The main drugs that have topoisomerase I as their target are camptothecins (CPTs) (Figure 1) but they suffer from several limitations in spite of being in clinical use.…”

Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site

“…The DNA gyrase is chiefly present in prokaryotes [ 3 ], where it catalyzes the cleavage of the two helices of a DNA strand in an ATP-dependent manner, making it essential for bacterial survival [ 4 ]. DNA gyrase is a validated pharmaceutical target for antibiotics [ 5 ], and some of its homologous human forms are targeted by several anticarcinogens [ 6 , 7 ].…”