PI-083

A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and antiproliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, β1 subunit), trypsin-like (T-L, β2 subunit) and chymotrypsin-like (ChT-L, β5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC50 values of 9.90 ± 0.61, 44.83 ± 4.23 and 22.27 ± 0.15 μM against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC50 = 12.47 ± 0.21, 53.12 ± 2.56 and 26.37 ± 0.5 μM), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC50 = 1.72 ± 0.14-20.8 ± 0.5 μM and compounds 13 and 28 were found to be the most active compounds with IC50 values of 1.79 ± 0.21 and 1.72 ± 0.14 μM, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions.

A series of novel non-peptide boronic acid derivatives were designed and synthesized via rational drug design principles. All target compounds were screened for the proteasome inhibitory activities in vitro. Selected compounds (6a and 7j) were evaluated for their cytotoxic activities in vitro. Among these tested compounds, two (6a, 7j) displayed better proteasome inhibitory activities than that of the lead compound PI-083, and compound 6a was the most potent one with IC₅₀ value of 161.90±29.46 nM. However, both of the two compounds (6a, 7j) exhibited weak cytotoxic activities, the discrepancy may lie in the compensatory pathways of the ubiquitin-proteasome pathway that promote tumor cell survival.

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.