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

SYSNO ASEP	0476531
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine
Author(s)	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}
Number of authors	7
Source Title	European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234 Roč. 135, JUL 28 (2017), s. 142-158
Number of pages	17 s.
Language	eng - English
Country	FR - France
Keywords	Apoptosis ; Inhibitor ; Proteasome ; Salicylamide ; Ubiquitin
Subject RIV	EB - Genetics ; Molecular Biology
OECD category	Biochemical research methods
R&D Projects	LO1204 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	UEB-Q - RVO:61389030
UT WOS	000403512100013
EID SCOPUS	85018470778
DOI	10.1016/j.ejmech.2017.04.027
Annotation	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.
Workplace	Institute of Experimental Botany
Contact	David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469
Year of Publishing	2018

Number of the records: 1