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

Chem Biol Drug Des. 2023 Jun;101(6):1283-1298. doi: 10.1111/cbdd.14212. Epub 2023 Feb 17.

Abstract

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.

Keywords: anilide; antiproliferative activity; glycine; molecular modeling; naphthoquinone; noncovalent; proteasome inhibitor; synthesis; β-alanine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Antineoplastic Agents* / pharmacology
  • Cell Proliferation
  • Glycine / pharmacology
  • Molecular Structure
  • Naphthoquinones* / chemistry
  • Naphthoquinones* / pharmacology
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology
  • Structure-Activity Relationship
  • beta-Alanine / pharmacology

Substances

  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex
  • Glycine
  • Naphthoquinones
  • beta-Alanine
  • Anilides
  • Antineoplastic Agents