Acta Pharmaceutica, Vol. 73 No. 3, 2023.
Original scientific paper
https://doi.org/10.2478/acph-2023-0032
Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome
MARTINA GOBEC
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
ALEŠ OBREZA
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
MARKO JUKIČ
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia; University of Maribor, Faculty of Chemistry and Chemical Engineering, Laboratory of Physical Chemistry and Chemical Thermodynamics, Maribor SI-2000, Slovenia
ANA BAUMGARTNER
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
ANJA MIHELČIČ
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
ŠPELA POTOČNIK
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
JULIJA VIRANT
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
IRENA MLINARIČ RAŠČAN
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
STANISLAV GOBEC
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
IZIDOR SOSIČ
; University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
Abstract
The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as cancer, inflammation, and autoimmune diseases. The development of novel chemical scaffolds of non-peptidic nature, capable of inhibiting different catalytically active subunits of both isoforms, is a viable approach against these diseases. Such compounds are also useful as leads for the development of biochemical probes that enable the studies of the roles of both isoforms in various biological contexts. Here, we present a ligand-based computational design of (immuno)proteasome inhibitors, which resulted in the amino-substituted N-arylpiperidine-based compounds that can inhibit different subunits of the (immuno)proteasome in the low micromolar range. The compounds represent a useful starting point for further structure-activity relationship studies that will, hopefully, lead to non-peptidic compounds that could be used in pharmacological and biochemical studies of both proteasomes.
Keywords
proteasomes; scaffold morphing; optimization; computational design; selectivity; inhibitors
Hrčak ID:
305547
URI
Publication date:
30.9.2023.
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