Design, synthesis and biological evaluation of novel non-peptide boronic acid derivatives as proteasome inhibitors.
A novel series of non-peptide proteasome inhibitors bearing the 1, 4-naphthoquinone scaffold and boronic acid warhead was developed. In the biological evaluation on the chymotrypsin-like activity of human 20S proteasome, five compounds showed IC50values in the nanomolar range. Docking experiments into the yeast 20S proteasome rationalized their biological activities and allowed further optimization of this interesting class of inhibitors. Within the cellular proliferation inhibition assay and western blot analysis, compound 3e demonstrated excellent anti-proliferative activity against solid tumor cells and clear accumulation of ubiquitinated cellular proteins. Furthermore, in the microsomal stability assay compound 3e demonstrated much improved metabolic stability compared to bortezomib, emerging as a promising lead compound for further design of non-peptide proteasome inhibitors.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Ying
Y
Ge
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Aibo
A
Li
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Jianwei
J
Wu
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Haiwei
H
Feng
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Letian
L
Wang
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Hongwu
H
Liu
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Yungen
Y
Xu
Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Nanjing 210008, China. Electronic address: xqx008dg@sina.com.
Qingxiang
Q
Xu
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhaolicpu@126.com.
Li
L
Zhao
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yuyanli@cpu.edu.cn.
Yuyan
Y
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000737:chemistry*; D000069286:Bortezomib / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004151:Dipeptides; C000617097:N-(1,4-naphthoquinon-2-yl)-L-phenylalanine-L-boronoleucine; D009285:Naphthoquinones; D061988:Proteasome Inhibitors; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
1, 4-naphthoquinones; Docking studies; Non-peptide boronic acid; Proteasome inhibitors