Počet záznamů: 1
Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine
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SYSNO ASEP 0476531 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Synthesis 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, ORCIDCelkový počet autorů 7 Zdroj.dok. European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 135, JUL 28 (2017), s. 142-158Poč.str. 17 s. Jazyk dok. eng - angličtina Země vyd. FR - Francie Klíč. slova Apoptosis ; Inhibitor ; Proteasome ; Salicylamide ; Ubiquitin Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Biochemical research methods CEP LO1204 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UEB-Q - RVO:61389030 UT WOS 000403512100013 EID SCOPUS 85018470778 DOI https://doi.org/10.1016/j.ejmech.2017.04.027 Anotace Inhibition 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. Pracoviště Ústav experimentální botaniky Kontakt David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Rok sběru 2018
Počet záznamů: 1