Discovery of Mono‐ and Disubstituted 1H‐Pyrazolo[3,4]pyrimidines and 9H‐Purines as Catalytic Inhibitors of Human DNA Topoisomerase IIα

Abstract

Human DNA topoisomerase IIα (htIIα) is a validated target for the development of anticancer agents. Based on structural data regarding the binding mode of AMP-PNP (5'-adenylyl-β,γ-imidodiphosphate) to htIIα, we designed a two-stage virtual screening campaign that combines structure-based pharmacophores and molecular docking. In the first stage, we identified several monosubstituted 9H-purine compounds and a novel class of 1H-pyrazolo[3,4]pyrimidines as inhibitors of htIIα. In the second stage, disubstituted analogues with improved cellular activities were discovered. Compounds from both classes were shown to inhibit htIIα-mediated DNA decatenation, and surface plasmon resonance (SPR) experiments confirmed binding of these two compounds on the htIIα ATPase domain. Proposed complexes and interaction patterns between both compounds and htIIα were further analyzed in molecular dynamics simulations. Two compounds identified in the second stage showed promising anticancer activities in hepatocellular carcinoma (HepG2) and breast cancer (MCF-7) cell lines. The discovered compounds are suitable starting points for further hit-to-lead development in anticancer drug discovery.

3‐substituted‐1H‐indazoles as Catalytic Inhibitors of the Human DNA Topoisomerase IIα

“…In our recent studies we focused on compounds that target the htIIα ATP binding site and successfully evaluated several chemical classes of inhibitors; 4‐aminotriazines ( 2‐3 ), triazin‐2‐ones (4‐ 5 ), as well as purines and pyrazolopyrimidines ( 6 ‐ 10 ) . Our present study represents a continuation of our ongoing efforts in the field of htIIα inhibitors.…”

“…Our present study represents a continuation of our ongoing efforts in the field of htIIα inhibitors. We used our previously discovered pyrazolopyrimidine and purine‐based compounds ( 6 ‐ 10 ) as a starting point for the ligand‐based drug design in an attempt to improve the potency, as well as to probe for a novel chemical class and thus expand the chemical space of htIIα catalytic inhibitors that target the ATP binding site.…”

Exploration of the Chemistry and Biological Properties of Pyrimidine as a Privilege Pharmacophore in Therapeutics

“…1,2,3,4tetra hydropyrimidine analogue was found to be potent against various human cancer cell lines (Bari et al, 2015). Triazolo-pyrimidinone (Mohamed et al, 2015b) and pyrazolo-pyrimidine (Pogorelcnik et al, 2015) with the structures shown in Fig. 40, revealed promising anticancer activities compared to the activity of the commonly used anticancer drug, doxorubicin in both MCF-7 and A549 cell lines.…”

Synthesis, Docking Studies and Anticancer Activity of New Substituted Pyrimidine and Triazolopyrimidine Glycosides

“…Drugs which affect DNA biosynthesis have received much attention and amongst them pyrimidine derivatives remain the most important (Cieplik, 1992;Pogorelcnik et al, 2015). Many pyrimidine incorporating compounds constitute an assortment of drugs with ability to hinder biosynthesis of pyrimidine nucleotides or act effectively as naturalist metabolites, thus interfering in substantial ellular processes, for example nucleic acids synthesis.…”

“…Synthesized glycosides and their derived analogs (Zhao et al, 2008;Zhao and Li, 2007) revealed considerable inhibitory activity of DNA-topoisomerase II (TopoII) that controls DNA topology by transitory cleavage of the DNA double helix, which was affirmed as important molecular target of anticancer drugs (Champoux, 2001;Pommier et al, 2010). Moreover, studied biological assays found that exotic sugar part confers a number of glycosides with best conformation possessing high binding affinities via hydrogen bonding to the entry of the ATPase pocket (Gui et al, 2011;Shi et al, 2012).…”