Počet záznamů: 1  

Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine

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    SYSNO ASEP0476531
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevSynthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine
    Tvůrce(i) Jorda, Radek (UEB-Q) ORCID, RID
    Dušek, J. (CZ)
    Řezníčková, Eva (UEB-Q) RID, ORCID
    Pauk, K. (CZ)
    Magar, P. P. (CZ)
    Imramovský, A. (CZ)
    Kryštof, Vladimír (UEB-Q) RID, ORCID
    Celkový počet autorů7
    Zdroj.dok.European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
    Roč. 135, JUL 28 (2017), s. 142-158
    Poč.str.17 s.
    Jazyk dok.eng - angličtina
    Země vyd.FR - Francie
    Klíč. slovaApoptosis ; Inhibitor ; Proteasome ; Salicylamide ; Ubiquitin
    Vědní obor RIVEB - Genetika a molekulární biologie
    Obor OECDBiochemical research methods
    CEPLO1204 GA MŠk - Ministerstvo školství, mládeže a tělovýchovy
    Institucionální podporaUEB-Q - RVO:61389030
    UT WOS000403512100013
    EID SCOPUS85018470778
    AnotaceInhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI 50 values. The most potent compounds (series 4 and 6) were further assayed for their inhibition of chymotrypsin-like protease activity of the 26S proteasome in U266 cells. The majority of compounds inhibited the proteasome in mid-nanomolar concentrations (IC 50 ranging from 57 to 197 nM) and it correlated with cellular potency. In a cell based assay involving green fluorescence protein (GFP) fused to a short degron that is rapidly degraded by a proteasome the compounds induced accumulation of GFP, visualised and quantified by live-cell imaging. Levels of polyubiquitinated proteins in U266 cells treated by compound 4m were also analyzed by immunoblotting, revealing a typical high molecular mass smear of ubiquitin conjugates. Finally, apoptotic cell death in treated U266 cells was detected biochemically by measuring the activity of caspases 3 and 7 in lysates and by immunoblotting of caspase 7, its substrate poly(ADP-ribose)polymerase, and Mcl-1, which all together showed changes typical for apoptosis. All these observations were in agreement with expected cellular mechanism of action and confirmed proteasome targeting by prepared O-benzyl salicylamides.
    PracovištěÚstav experimentální botaniky
    KontaktDavid Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469
    Rok sběru2018
Počet záznamů: 1