The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds

Abstract

Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. In order to find stronger DNA binding and more potent cytotoxic compounds, a series of ester-coupled bisanthrapyrazole derivatives of 7-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethyl]anthra[1,9-cd]pyrazol-6(2H)-one (AP9) were designed and evaluated by molecular docking techniques. Because the anthrapyrazoles are unable to be reductively activated like doxorubicin and other anthracyclines, they should not be cardiotoxic like the anthracyclines. Based on the docking scores of a series of bisanthrapyrazoles with different numbers of methylene linkers (n) that were docked into an X-ray structure of double-stranded DNA, five bisanthrapyrazoles (n = 1 to 5) were selected for synthesis and physical and biological evaluation. The synthesized compounds were evaluated for DNA binding and bisintercalation by measuring the DNA melting temperature increase, for growth inhibitory effects on the human erythroleukemic K562 cell line, and for DNA topoisomerase IIα-mediated cleavage of DNA and inhibition of DNA topoisomerase IIα decatenation activities. The results suggest that the bisanthrapyrazoles with n = 2 to 5 formed bisintercalation complexes with DNA. In conclusion, a novel group of bisintercalating anthrapyrazole compounds have been designed, synthesized and biologically evaluated as possible anticancer agents.

The structure-based design, synthesis, and biological evaluation of DNA-binding amide linked bisintercalating bisanthrapyrazole anticancer compounds

“…9 The bisanthrapyrazoles 1, 4, and 5 all increased DT m about the same as the parent 6. In our previous study on the analogous ester-linked bisanthrapyrazoles 4 we showed that the slope of a plot of DT m versus drug concentration for a bisintercalator is approximately twice that of the monomeric monointercalator 6. This is due to the bisintercalator occupying twice the number of intercalation sites on the DNA as had been previously shown from a comparison of the bisintercalator dye YOYO and its monomeric form YO-PRO.…”

“…Following this we used molecular modeling to design and synthesize a series of bisanthrapyrazoles that contained a diester linkage joining two anthrapyrazoles together. 4 However, the biological data on these bisanthrapyrazoles suggested that the ester linkages were susceptible to hydrolysis, possibly through the action of cellular esterases. 4 We showed that these bisanthrapyrazoles had good cell growth inhibitory activity and the compounds with two or more methylene linkers formed bisintercalation complexes with DNA.…”

“…4 However, the biological data on these bisanthrapyrazoles suggested that the ester linkages were susceptible to hydrolysis, possibly through the action of cellular esterases. 4 We showed that these bisanthrapyrazoles had good cell growth inhibitory activity and the compounds with two or more methylene linkers formed bisintercalation complexes with DNA. 4 In the present work we attempted to improve the stability of these compounds by replacing the ester linkage with the much more stable amide linkage (Fig.…”

“…4 We showed that these bisanthrapyrazoles had good cell growth inhibitory activity and the compounds with two or more methylene linkers formed bisintercalation complexes with DNA. 4 In the present work we attempted to improve the stability of these compounds by replacing the ester linkage with the much more stable amide linkage (Fig. 1, compounds 1-5).…”

“…Compound 6 ( Fig. 1), which we previously had shown to have significant cell growth and topoisomerase IIa inhibitory activity, 3,4 was chosen as the scaffold for the synthesis of a series of the bisanthrapyrazole congeners. In addition to measuring the cell growth inhibitory effects of the bisanthrapyrazoles we also measured their ability to bind to DNA, to inhibit topoisomerase IIa, and to cause topoisomerase IIamediated DNA cleavage.…”