Title of article :
Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors Original Research Article
Author/Authors :
Yongqiang Zhu، نويسنده , , Shuyang Yao، نويسنده , , Bo Xu، نويسنده , , Zemei Ge، نويسنده , , Jingrong Cui، نويسنده , , Tieming Cheng، نويسنده , , Runtao Li، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2009
Pages :
11
From page :
6851
To page :
6861
Abstract :
A series of tripeptide boronate proteasome inhibitors were designed and synthesized on the basis of our previously built tripeptide aldehyde 3D-QSAR models. All the synthesized compounds were evaluated for their proteasome-inhibitory activities in an isolated 20S rabbit proteasome, and selected compounds were evaluated for their antitumor activities in vitro against four human cancer cell lines. Biological results showed bulky and negative substituents at P2 position improved the proteasome-inhibitory potency obviously, which completely conformed to the theoretical models, while those at P3 position thoroughly deviated from the 3D-QSAR model. Most of the screened compounds showed less than 1 nM inhibitory potency and high selectivity against 20S proteasome, of which 7f is the most potent (IC50 = 0.079 nM) and twofold more active than bortezomib (IC50 = 0.161 nM). Cell viability indicated hydrophilic 4-hydroxyphenyl substituent at P2 or P3 position was not favorable to the cellular activities. Especially for the two hematologic cancer cell lines, HL-60 and U266, 7f inhibited them at the level of less than 10 nM and was more potent than the control bortezomib. It is being considered a promising new lead to be developed for the treatment of various cancers.
Keywords :
Proteasome inhibitor , Tripeptide boronic acid , drug design , Synthesis
Journal title :
Bioorganic and Medicinal Chemistry
Serial Year :
2009
Journal title :
Bioorganic and Medicinal Chemistry
Record number :
1306381
Link To Document :
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