Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase IIα.

Kaja Bergant Loboda, Katja Valjavec, Martina Štampar, Gerhard Wolber, Bojana Žegura, Metka Filipič, Marija Sollner Dolenc, Andrej Perdih

Bioorganic chemistry 2020 Jun

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Cancer constitutes a group of diseases linked to abnormal cell growth that can potentially spread to other parts of the body and is one of the most common causes of death. The molecular motors - DNA topoisomerases - that enable topological changes of the DNA molecule are one of the most established targets of cancer therapies. Due to known limitations of established topo II poisons such as cardiotoxicity, induction of secondary malignancies and recognized cancer cell resistance, an emerging group of catalytic topo II inhibitors attempts to circumvent these challenges. Currently, this approach comprises several subgroups of mechanistically diverse inhibitors, one of which are compounds that act by binding to their ATPase domain. In this study we have designed, synthesized and characterized a new series of 3,5-substituted 1,2,4-oxadiazoles that act as catalytic inhibitors of human topo IIα. The introduction of the substituted rigid substitutions on the oxadiazole backbone was intended to enhance the interactions with the ATP binding site. In the inhibition assays selected compounds revealed a new class of catalytic inhibitors targeting this molecular motor and showed binding to the isolated topo IIα ATPase domain. The predicted inhibitor binding geometries were evaluated in molecular dynamics simulations and subsequently dynophore models were derived, which provided a deeper insight into molecular recognition with its macromolecular target. Selected compounds also displayed in vitro cytotoxicity on the investigated MCF-7 cancer cell line and did not induce double-strand breaks (DSB), thus displaying a mechanism of action diverse from the topo II poisons also on the cellular level. The substituted oxadiazoles thus comprise a chemical class of interesting compounds that are synthetically fully amenable for further optimization to anticancer drugs. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Kaja Bergant Loboda, Katja Valjavec, Martina Štampar, Gerhard Wolber, Bojana Žegura, Metka Filipič, Marija Sollner Dolenc, Andrej Perdih. Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase IIα. Bioorganic chemistry. 2020 Jun;99:103828