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

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, ORCID}
Celkový počet autorů	7
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. 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	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