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Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase ▫$II\alpha$▫
ID Bergant Loboda, Kaja (Author), ID Valjavec, Katja (Author), ID Štampar, Martina (Author), ID Wolber, Gerhard (Author), ID Žegura, Bojana (Author), ID Filipič, Metka (Author), ID Sollner Dolenc, Marija (Author), ID Perdih, Andrej (Author)

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Abstract
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 II[alpha] . 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 II[alpha] 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.

Language:English
Keywords:human DNA topoisomerase II[alpha], catalytic inhibitors, drug design, oxadiazoles, anticancer agents
Work type:Article (dk_c)
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Year:2020
Publication status in journal:Published
Article version:Publisher's version of article
Number of pages:Str. 103828-1 - 103828-19
Numbering:art. 103828, Vol. 99
PID:20.500.12556/RUL-141903 This link opens in a new window
UDC:615.4:54:577.27
ISSN on article:0045-2068
DOI:10.1016/j.bioorg.2020.103828 This link opens in a new window
COBISS.SI-ID:4900977 This link opens in a new window
Publication date in RUL:11.10.2022
Views:69
Downloads:31
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Record is a part of a journal

Title:Bioorganic chemistry
Shortened title:Bioorg. chem.
Publisher:Elsevier
ISSN:0045-2068
COBISS.SI-ID:25099008 This link opens in a new window

Secondary language

Language:Slovenian
Keywords:topoizomeraza II[alfa], človeška DNK, zaviralci katalize, protirakave učinkovine

Projects

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Funding programme:Javna agencija Republike Slovenije za raziskovalno dejavnost
Project number:P1-0012-2019
Name:Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Funding programme:Javna agencija Republike Slovenije za raziskovalno dejavnost
Project number:P1-0208-2015
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Funding programme:Javna agencija Republike Slovenije za raziskovalno dejavnost
Project number:P1-0245-2019
Name:Ekotoksiologija, toksikološka genomika in karcinogeneza

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