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Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents

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dc.abstract.enCurrently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, (12aS)-8,9-dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione and (12aS)-8-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell lines when compared to our previously reported compounds, with IC50 values in the range of 2.9-5.6 μM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC50 =6.1 μM) and MV-4-11 (IC50 =11.0 μM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC50 =31.8-55.0 μM) and very weak cytotoxic effect toward the Balb/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had Ki values of 10-19 μM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorTrzybiński, Damian
dc.contributor.authorWilczek, Marcin
dc.contributor.authorBieszczad, Bartosz
dc.contributor.authorDziełak, Monika
dc.contributor.authorWińska, Patrycja
dc.contributor.authorWoźniak, Krzysztof
dc.contributor.authorSiedlecki, Paweł
dc.contributor.authorMieczkowski, Adam
dc.contributor.authorFrączyk, Tomasz
dc.contributor.authorPSURSKI, MATEUSZ
dc.contributor.authorBagiński, Maciej
dc.date.accessioned2024-01-24T21:33:21Z
dc.date.available2024-01-24T21:33:21Z
dc.date.issued2021
dc.description.financePublikacja bezkosztowa
dc.description.number1
dc.description.volume18
dc.identifier.doi10.1002/CBDV.202000733
dc.identifier.issn1612-1872
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/104595
dc.identifier.weblinkhttps://onlinelibrary.wiley.com/doi/full/10.1002/cbdv.202000733
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofChemistry and Biodiversity
dc.relation.pagese2000733
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.subject.enautotaxin inhibition
dc.subject.enbenzodiazepines
dc.subject.encytotoxic agents
dc.subject.endrug design
dc.subject.enselectivity
dc.titleDesign and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents
dc.typeJournalArticle
dspace.entity.typePublication