3D-QSAR-aided design, synthesis, in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies.
Proteasome had been clinically validated as an effective target for the treatment of cancers. Up to now, many structurally diverse proteasome inhibitors were discovered. And two of them were launched to treat multiple myeloma (MM) and mantle cell lymphoma (MCL). Based on our previous biological results of dipeptidyl boronic acid proteasome inhibitors, robust 3D-QSAR models were developed and structure-activity relationship (SAR) was summarized. Several structurally novel compounds were designed based on the theoretical models and finally synthesized. Biological results showed that compound 12e was as active as the standard bortezomib in enzymatic and cellular activities. In vivo pharmacokinetic profiles suggested compound 12e showed a long half-life, which indicated that it could be administered intravenously. Cell cycle analysis indicated that compound 12e inhibited cell cycle progression at the G2M stage.
College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China.
Meng
M
Lei
College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China.
Huayun
H
Feng
College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China.
Cheng
C
Wang
College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China.
Hailing
H
Li
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China.
Jingmiao
J
Shi
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China.
Jia
J
Wang
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China.
Zhaogang
Z
Liu
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China.
Shanshan
S
Chen
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China.
Shihe
S
Hu
College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China. Electronic address: zhyqscu@hotmail.com.
Yongqiang
Y
Zhu
D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
3D-QSAR; Cell cycle; Pharmacokinetic; Proteasome inhibitor