Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors.
Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors.
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DOI：
10.1016/j.bmc.2009.08.023
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发表时间：
2009-10
影响因子：
3.5
通讯作者：
Yongqiang Zhu;Shuyang Yao;Bo Xu;Z. Ge;J. Cui;T. Cheng;Runtao Li
中科院分区：
文献类型：
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作者：
Yongqiang Zhu;Shuyang Yao;Bo Xu;Z. Ge;J. Cui;T. Cheng;Runtao Li
在构建的三肽醛3D-QSAR模型的基础上，设计合成了一系列硼酸三肽蛋白酶体抑制剂。所有合成的化合物在分离的20S兔蛋白酶体中进行了蛋白酶体抑制活性的评价，并对选定的化合物在体外对四种人类癌细胞的抗肿瘤活性进行了评价。生物学结果显示，p2位置的大体积和负取代基明显提高了蛋白酶体的抑制效力，这与理论模型完全吻合，而p3位置的取代基则完全偏离了3D-QSAR模型。筛选到的化合物对20S蛋白酶体的抑制效价大多小于1nM，且具有较高的选择性，其中7f的抑制效价最高（IC50=0.079nM），活性是硼替佐米（IC50=0.161 nM）的2倍。细胞活力表明亲水的4-羟基苯基取代基在p2或p3位置不利于细胞活性。特别是对HL-60和U266两种血液学癌细胞，7f的抑制作用在小于10nM的水平，且比对照硼替佐米更有效。它被认为是一种很有前途的治疗各种癌症的新先导物。
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 P2position improved the proteasome-inhibitory potency obviously, which completely conformed to the theoretical models, while those at P3position thoroughly deviated from the 3D-QSAR model. Most of the screened compounds showed less than 1nM inhibitory potency and high selectivity against 20S proteasome, of which 7f is the most potent (IC50=0.079nM) and twofold more active than bortezomib (IC50=0.161 nM). Cell viability indicated hydrophilic 4-hydroxyphenyl substituent at P2or P3position 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 10nM 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.