作用于polo-box结构域的拟肽类polo样激酶1抑制剂的设计、合成及其生物活性  

Design,synthesis and evaluation of peptidomimetics targeting the polo-box domain of polo-like kinase 1

作　　者：李芝艳 刘婕 李冰艳 江程[1,2,3] LI Zhiyan;LIU Jie;LI Bingyan;JIANG Cheng(Jiangsu Key Laboratory of Drug Design and Optimization,China Pharmaceutical University,Nanjing 210009;Key Laboratory on Protein Chemistry and Structural Biology,China Pharmaceutical University,Nanjing 210009;Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国药科大学江苏省药物分子设计与成药性优化重点实验室,南京210009 [2]中国药科大学蛋白质化学与结构生物学重点实验室,南京210009 [3]中国药科大学药学院药物化学系,南京210009

出　　处：《中国药科大学学报》2020年第3期287-294,共8页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81573278);2017年江苏省高等学校优秀科技创新团队资助项目。

摘　　要：为寻找新型的作用于polo-box结构域的拟肽类polo样激酶1(Plk1 PBD)抑制剂,将先导化合物(PLHSpT)结构中的磷酸基团替换为羧基,并采用非天然氨基酸进一步改造与优化,设计合成了一系列不含磷酸基团的拟肽类Plk1 PBD抑制剂(化合物7a^7u)。设计合成的21个拟肽类化合物均对Plk1 PBD抑制作用较强,其中化合物7l高选择性地抑制Plk1 PBD,IC50为0.285μmol/L,体外对HeLa肿瘤细胞株的生长抑制作用优于含磷酸基团的化合物。经过非天然氨基酸修饰和改造,化合物在大鼠血浆中的稳定性得到了提高。实验证明,用羧基替换磷酸基团并进行肽链的结构改造,可以获得成药性更好的选择性Plk1 PBD抑制剂。To identify novel inhibitors targeting the polo-box domain of polo-like kinase 1(Plk1 PBD),a series of new peptidomimetics(7 a-7 u) without phosphate group were designed and synthesized,where the phosphate group in the structure of the selective Plk1 PBD inhibitor PLHSpT was replaced by the carboxyl group,and the unnatural amino acids were applied for further modification and optimization.The 21 peptidomimetic compounds designed and synthesized had a strong inhibitory effect on Plk1 PBD,of which compound 71 highly selectively inhibited Plk1 PBD with IC50 of 0.285 μmol/L.The growth inhibition effect of HeLa tumor cell lines in vitro was better than that of compounds containing phosphate group.Moreover,the stability of the compound in rat plasma was improved by unnatural amino acids.Thus it is proved that selective Plk1 PBD inhibitor with improved characters can be obtained by replacing the phosphate group with a carboxyl group and restructuring the peptide chain.

关 键 词：Plk1 PBD 抑制剂 合成 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]