3D-QSAR-aided design,synthesis,in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies
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.
引文