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

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

doi:10.1016/j.bioorg.2020.103828

Cited by 13 publications

(14 citation statements)

References 66 publications

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“…The assay of all compounds 1 – 14 was performed as described previously. , The assay was performed at four different concentrations of inhibitors: 7.8, 31.25, 125, and 500 μM. The IC 50 values were calculated using GraphPad Prism 6.0 software and are shown as the concentrations of tested compounds where the residual activity of the enzyme was 50% .…”

Section: Experimental Sectionmentioning

confidence: 99%

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Substituted 4,5′-Bithiazoles as Catalytic Inhibitors of Human DNA Topoisomerase IIα

Loboda

Janežič

Štampar

et al. 2020

J. Chem. Inf. Model.

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Human type II topoisomerases, molecular motors that alter the DNA topology, are a major target of modern chemotherapy. Groups of catalytic inhibitors represent a new approach to overcome the known limitations of topoisomerase II poisons such as cardiotoxicity and induction of secondary tumors. Here, we present a class of substituted 4,5′-bithiazoles as catalytic inhibitors targeting the human DNA topoisomerase IIα. Based on a structural comparison of the ATPase domains of human and bacterial type II topoisomerase, a focused chemical library of 4,5′-bithiazoles was assembled and screened to identify compounds that better fit the topology of the human topo IIα adenosine 5′-triphosphate (ATP) binding site. Selected compounds showed inhibition of human topo IIα comparable to that of the etoposide topo II drug, revealing a new class of inhibitors targeting this molecular motor. Further investigations showed that compounds act as catalytic inhibitors via competitive ATP inhibition. We also confirmed binding to the truncated ATPase domain of topo IIα and modeled the inhibitor molecular recognition with molecular simulations and dynophore models. The compounds also displayed promising cytotoxicity against HepG2 and MCF-7 cell lines comparable to that of etoposide. In a more detailed study with the HepG2 cell line, there was no induction of DNA double-strand breaks (DSBs), and the compounds were able to reduce cell proliferation and stop the cell cycle mainly in the G1 phase. This confirms the mechanism of action of these compounds, which differs from topo II poisons also at the cellular level. Substituted 4,5′-bithiazoles appear to be a promising class for further development toward efficient and potentially safer cancer therapies exploiting the alternative topo II inhibition paradigm.

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Section: Experimental Sectionmentioning

confidence: 99%

“…We performed the assay in collaboration with Inspiralis (Norwich, U.K.). We examined selected compounds 1 , 9 , and reference compound etoposide at concentrations 3.9, 31.5, 125, and 500 μM, as described previously. , …”

Section: Experimental Sectionmentioning

confidence: 99%

Substituted 4,5′-Bithiazoles as Catalytic Inhibitors of Human DNA Topoisomerase IIα

Loboda

Janežič

Štampar

et al. 2020

J. Chem. Inf. Model.

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“…We then analyzed the aligned density clouds representing the pharmacophore features as shown With dynophores, we could point out the key residues involved in the interactions that persist through most of the simulation time. Already, from the previously designed inhibitors [37,[44][45][46], we recognized Asn120 as the key amino acid residue, exhibiting an anchor-like function via hydrogen bonding. Additional intermolecular interactions in the adenine portion of the binding pocket were found with the amino acid residues Asn91, Asn95, and Thr215; lipophilic interactions with the hydrophobic pocket enclosed by Ile125, Ile141, and Phe142; H-bond interactions in the sugar portion of the pocket with residues Ser148, Ser149, and Asn150.…”

Section: Dynophore-based Molecular Design Strategymentioning

confidence: 99%

“…They were included in docking because previous studies suggest they play an important role in binding of the native molecule [46,66]. The AMP-PNP molecule was docked into the defined active site by applying the following parameters of the GOLD genetic algorithm (GA): population size = 100, selection pressure = 1.1, No.…”

Section: Molecular Docking Calculationsmentioning

confidence: 99%

“…Different spin states of the water molecules W924 and W931 were allowed during docking. As in previously published studies performed at with this structure [46], to ensure that interactions similar to the interaction pattern of the purine moiety in the co-crystallized AMP-PNP molecule would be obtained, an H-bond constraint was added to Asn120. The GoldScore scoring function was used.…”

Section: Molecular Docking Calculationsmentioning

confidence: 99%

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Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα

Janežič

Valjavec

Loboda

et al. 2021

IJMS

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In this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the static structure-based-pharmacophore information with a dynamic component. Subsequently, derived pharmacophore models were employed in a virtual screening campaign of a library of natural compounds. Experimental evaluation identified flavonoid compounds with promising topoisomerase IIα catalytic inhibition and binding studies confirmed interaction with the ATPase domain. We constructed a binding model through docking and extensively investigated it with molecular dynamics MD simulations, essential dynamics, and MM-GBSA free energy calculations, thus reconnecting the new results to the initial dynophore-based screening model. We not only demonstrate a new design strategy that incorporates a dynamic component of molecular recognition, but also highlight new derivates in the established flavonoid class of topoisomerase II inhibitors.

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A comprehensive review of recent advances in the biological activities of 1,2,4‐oxadiazoles

Hendawy

2022

Archiv der Pharmazie

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Nitrogen heterocycles play an essential role in medication development. The 1,2,4‐oxadiazole heterocycle has been extensively studied, yielding a large variety of molecules with varied biological functions. The 1,2,4‐oxadiazole shows bioisosteric equivalency with ester and amide moieties. In recent years, the 1,2,4‐oxadiazole nucleus has received a lot of attention in medicinal chemistry. It was thought to be a pharmacophore component in the production of biologically intriguing drugs. This review presents a comprehensive overview of the recent achievements in the biological activities of 1,2,4‐oxadiazoles as potential antimicrobial, anticancer, anti‐inflammatory, neuroprotective, and antidiabetic agents. The structure–activity relationship and mechanisms of action are also reviewed.

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

Cited by 13 publications

References 66 publications

Substituted 4,5′-Bithiazoles as Catalytic Inhibitors of Human DNA Topoisomerase IIα

Substituted 4,5′-Bithiazoles as Catalytic Inhibitors of Human DNA Topoisomerase IIα

Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα

A comprehensive review of recent advances in the biological activities of 1,2,4‐oxadiazoles

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