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

A series of novel noncovalent glycine/beta- 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 mu M and most of them exhibited inhibitory efficacy with varying ratios against the three catalytic subunits (beta 1, beta 2, and beta 5) 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 beta 5 subunit compared with beta 1 and beta 2 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 mu M, respectively. Additionally, compound 7 displayed comparable potency to PI -083 lead compound in terms of beta 5 antiproteasomal activity with an inhibition percentage of 34.67 at 10 mu M. This compound showed an IC50 value of 32.30 +/- 0.45 mu M against beta 5 subunit. Furthermore, molecular modeling studies of the most active compound 7 revealed key interactions with beta 5 subunit. The results suggest that this class of compounds may be beneficial for the development of new potent proteasome inhibitors.

Automated summary

A series of novel noncovalent glycine/beta-alanine anilide derivatives with 2-chloronaphthoquinone structure were designed, synthesized, and evaluated for their antiproliferative and antiproteasomal activities against MCF-7 cell line. The target compounds showed antiproliferative activity in the range of IC50 = 7.10 +/- 0.10-41.08 +/- 0.14 μM and exhibited inhibitory efficacy against the catalytic subunits of proteasome. Among the compounds, compounds 7 and 9 showed the highest antiproliferative activity, and compound 7 displayed comparable potency in terms of beta 5 antiproteasomal activity.