Design, synthesis, and biological evaluation of some novel naphthoquinone‐glycine/β‐alanine anilide derivatives as noncovalent proteasome inhibitors

A series of novel noncovalent glycine/β‐alanine anilide derivatives possessing 2‐chloronaphthoquinone structure as a pharmacophoric unit were designed, synthesized, and evaluated for their antiproliferative and antiproteasomal activities against MCF‐7 cell line, in vitro. According to biological act...

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Published in:Chemical biology & drug design 2023-06, Vol.101 (6), p.1283-1298
Main Authors: Tatar, Irem, Uysal, Sirin, Yilmaz, Sinem, Tarikogullari, Ayse H., Ballar Kirmizibayrak, Petek, Soyer, Zeynep
Format: Article
Language:English
Subjects:
anilide
Anilides - pharmacology
Antineoplastic Agents - pharmacology
antiproliferative activity
beta-Alanine - pharmacology
Cell Proliferation
glycine
Glycine - pharmacology
molecular modeling
Molecular Structure
naphthoquinone
Naphthoquinones - chemistry
Naphthoquinones - pharmacology
noncovalent
Proteasome Endopeptidase Complex
proteasome inhibitor
Proteasome Inhibitors - chemistry
Proteasome Inhibitors - pharmacology
Structure-Activity Relationship
synthesis
β‐alanine
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Summary:A series of novel noncovalent glycine/β‐alanine anilide derivatives possessing 2‐chloronaphthoquinone structure as a pharmacophoric unit were designed, synthesized, and evaluated for their antiproliferative and antiproteasomal activities against MCF‐7 cell line, in vitro. According to biological activity results, all the target compounds showed antiproliferative activity in the range of IC50 = 7.10 ± 0.10–41.08 ± 0.14 μM and most of them exhibited inhibitory efficacy with varying ratios against the three catalytic subunits (β1, β2, and β5) presenting caspase‐like (C‐L), trypsin‐like (T‐L) and chymotrypsin‐like (ChT‐L) activities of proteasome. The antiproteasomal activity evaluations revealed that compounds preferentially inhibited the β5 subunit compared with β1 and β2 subunits of the proteasome. Among the compounds, compounds 7 and 9 showed the highest antiproliferative activity with an IC50 value of 7.10 ± 0.10 and 7.43 ± 0.25 μM, respectively. Additionally, compound 7 displayed comparable potency to PI‐083 lead compound in terms of β5 antiproteasomal activity with an inhibition percentage of 34.67 at 10 μM. This compound showed an IC50 value of 32.30 ± 0.45 μM against β5 subunit. Furthermore, molecular modeling studies of the most active compound 7 revealed key interactions with β5 subunit. The results suggest that this class of compounds may be beneficial for the development of new potent proteasome inhibitors. Novel naphthoquinone‐glycine/β‐alanine anilide derivatives were synthesized as proteasome inhibitors. Compound 7 exhibited the highest antiproliferative and β5 antiproteasomal activity with IC50 values of 7.10 ± 0.10 and 32.3 ± 0.45 μM, respectively. The binding mechanism of compound 7 in complex with β5 subunit was carried out with molecular modeling studies.
ISSN:1747-0277
1747-0285
DOI:10.1111/cbdd.14212