Design, synthesis and biological evaluation of novel naphthoquinone-4-aminobenzensulfonamide/carboxamide derivatives as proteasome inhibitors

被引:14
作者
Uysal, Sirin [1 ]
Soyer, Zeynep [1 ]
Saylam, Merve [2 ]
Tarikogullari, Ayse H. [1 ]
Yilmaz, Sinem [3 ,4 ]
Kirmizibayrak, Petek Ballar [5 ]
机构
[1] Ege Univ, Fac Pharm, Dept Pharmaceut Chem, TR-35100 Izmir, Turkey
[2] Izmir Katip Celebi Univ, Fac Pharm, Dept Pharmaceut Chem, Izmir, Turkey
[3] Ege Univ, Inst Sci, Dept Biotechnol, Izmir, Turkey
[4] Univ Alaaddin Keykubat, Fac Engn, Dept Bioengn, Antalya, Turkey
[5] Ege Univ, Fac Pharm, Dept Biochem, Izmir, Turkey
关键词
Proteasome inhibitor; Antiproliferative activity; Naphthoquinone; Sulfonamide/carboxamide; Molecular docking; Synthesis; 20S PROTEASOME; GENETIC ALGORITHM; UBIQUITIN; CANCER; GENERATION; RESOLUTION; PARTICLE; SERIES;
D O I
10.1016/j.ejmech.2020.112890
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and anti-proliferative 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, beta 1 subunit), trypsin-like (T-L, beta 2 subunit) and chymotrypsin-like (ChT-L, beta 5 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 mu M 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 mu M), 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 mu M 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 mu M, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions. (c) 2020 Elsevier Masson SAS. All rights reserved.
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页数:15
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