Han Liqiang, Wen Yanzhao, Li Ridong, Xu Bo, Ge Zemei, Wang Xin, Cheng Tieming, Cui Jingrong, Li Runtao
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
Bioorg Med Chem. 2017 Aug 1;25(15):4031-4044. doi: 10.1016/j.bmc.2017.05.049. Epub 2017 Jun 9.
On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors.
基于脯氨酸 - 硼酸作为药效团在激酶抑制剂中的应用以及我们之前的研究结果，以脯氨酸 - 硼酸为弹头，设计并合成了两个系列的肽脯氨酸 - 硼酸，即二肽脯氨酸 - 硼酸（I）和三肽脯氨酸 - 硼酸（II）。首先对所有合成化合物针对MGC803细胞的生物活性进行评估，然后选择最佳化合物II - 7测试其对六种人类肿瘤细胞系的抗肿瘤谱以及对三个亚基的蛋白酶体抑制作用。结果表明，系列II的生物活性比系列I好得多。化合物II - 7不仅在细胞和蛋白酶体模型中均表现出优异的生物活性，IC值达到纳摩尔水平，而且具有更好的亚基选择性。因此，以脯氨酸 - 硼酸作为弹头在蛋白酶体抑制剂的设计中是合理的。
