3D-QSAR-aided design,synthesis,in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies
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- 英文论文题名：3D-QSAR-aided design,synthesis,in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies
- 论文作者：Meng Lei ; Huayun Feng ; Cheng Wang ; Hailing Li ; Jingmiao Shi ; Jia Wang ; Zhaogang Liu ; Shanshan Chen ; Shihe Hu ; Yongqiang Zhu
- 英文论文作者：Meng Lei ; Huayun Feng ; Cheng Wang ; Hailing Li ; Jingmiao Shi ; Jia Wang ; Zhaogang Liu ; Shanshan Chen ; Shihe Hu ; Yongqiang Zhu ; Nanjing Forestry University ; Nanjing Normal University ; Jiangsu Chia Tai Fenghai Pharmaceutical Co.Ltd.
- 年：2016
- 作者机构：Nanjing Forestry University;Nanjing Normal University;Jiangsu Chia Tai Fenghai Pharmaceutical Co.Ltd.;
- 英文论文关键词：3D-QSAR ; Proteasome inhibitor ; Pharmacokinetic ; Cell cycle
- 会议召开时间：2016-09-27
- 会议录名称：中国药学会第十三届青年药学科研成果交流会论文集
- 语种：英文
- 分类号：R91;R914.5
- 学会代码：YYWS
- 会议名称：中国药学会第十三届青年药学科研成果交流会
- 会议地点：中国江西南昌
- 主办单位：中国药学会
- 学会名称：中国药学会
- 页数：1
- 文件大小：38k
- 原文格式：O
- 会议级别：全国
摘要
Proteasome had been clinically validated as an effective target for the treatment of cancers.The high selectivity and low dissociation rates of boronic acids have placed these chemical compounds into the focus of medical research and drug development.Previously,a series of structurally novel dipeptidyl boronic acid proteasome inhibitors were synthesized and biologically evaluated by our group.To expand the structure diversity and quantitatively summarizing the structure-activity relationship(SAR) of the synthesized inhibitors,we firstly carried out 3D-QSAR studies with the methods of CoMFA(comparative molecule field analysis) and CoMSIA(comparative molecule similarity indices analysis) based on our own biological results.Then the SAR was summarized and several structurally diverse proteasome inhibitors were designed and synthesized.Biological results showed that compound 12 e was as active as the standard bortezomib in enzymatic and cellular activities.In vivo pharmacokinetic profiles suggested compound 12 e showed a long half-life,which indicated that it could be administered intravenously.Cell cycle analysis indicated that compound 12 e inhibited cell cycle progression at the G2 M stage.
Proteasome had been clinically validated as an effective target for the treatment of cancers.The high selectivity and low dissociation rates of boronic acids have placed these chemical compounds into the focus of medical research and drug development.Previously,a series of structurally novel dipeptidyl boronic acid proteasome inhibitors were synthesized and biologically evaluated by our group.To expand the structure diversity and quantitatively summarizing the structure-activity relationship(SAR) of the synthesized inhibitors,we firstly carried out 3D-QSAR studies with the methods of CoMFA(comparative molecule field analysis) and CoMSIA(comparative molecule similarity indices analysis) based on our own biological results.Then the SAR was summarized and several structurally diverse proteasome inhibitors were designed and synthesized.Biological results showed that compound 12 e was as active as the standard bortezomib in enzymatic and cellular activities.In vivo pharmacokinetic profiles suggested compound 12 e showed a long half-life,which indicated that it could be administered intravenously.Cell cycle analysis indicated that compound 12 e inhibited cell cycle progression at the G2 M stage.
Proteasome had been clinically validated as an effective target for the treatment of cancers.The high selectivity and low dissociation rates of boronic acids have placed these chemical compounds into the focus of medical research and drug development.Previously,a series of structurally novel dipeptidyl boronic acid proteasome inhibitors were synthesized and biologically evaluated by our group.To expand the structure diversity and quantitatively summarizing the structure-activity relationship(SAR) of the synthesized inhibitors,we firstly carried out 3D-QSAR studies with the methods of CoMFA(comparative molecule field analysis) and CoMSIA(comparative molecule similarity indices analysis) based on our own biological results.Then the SAR was summarized and several structurally diverse proteasome inhibitors were designed and synthesized.Biological results showed that compound 12 e was as active as the standard bortezomib in enzymatic and cellular activities.In vivo pharmacokinetic profiles suggested compound 12 e showed a long half-life,which indicated that it could be administered intravenously.Cell cycle analysis indicated that compound 12 e inhibited cell cycle progression at the G2 M stage.
引文