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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F17%3A00476531" target="_blank" >RIV/61389030:_____/17:00476531 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15310/17:73584165

Result on the web

<a href="http://dx.doi.org/10.1016/j.ejmech.2017.04.027" target="_blank" >http://dx.doi.org/10.1016/j.ejmech.2017.04.027</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2017.04.027" target="_blank" >10.1016/j.ejmech.2017.04.027</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10609 - Biochemical research methods

Project

<a href="/en/project/LO1204" target="_blank" >LO1204: Sustainable development of research in the Centre of the Region Haná</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Volume of the periodical

135

Issue of the periodical within the volume

JUL 28

Country of publishing house

FR - FRANCE

Number of pages

17

Pages from-to

142-158

UT code for WoS article

000403512100013

EID of the result in the Scopus database

2-s2.0-85018470778