Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Bioorg Med Chem. 2021 Jan 1;29:115867. doi: 10.1016/j.bmc.2020.115867. Epub 2020 Nov 9.
A series of non-covalent piperidine-containing peptidyl derivatives with various substituents at side chains of different residues were designed, synthesized and evaluated as proteasome inhibitors. After proteasome inhibitory evaluations of all the synthesized target compounds, selected ones were tested for their anti-proliferation activities against three multiple myeloma (MM) cell lines. 8 analogues displayed more potent activities than carfilzomib, and the most promising compound 24 showed IC values of 0.8 ± 0.2 nM against 20S proteasome and 8.42 ± 0.74 nM, 7.14 ± 0.52 nM, 14.20 ± 1.08 nM for RPMI 8226, NCI-H929 and MM.1S cell lines, respectively. Additionally, mechanisms of anti-cancer activity of representative compound 24 were further investigated. Apoptosis of RPMI-8226 cells were achieved through accumulating polyubiquitin and inducing the cleavage of caspase and PARP. Besides, half-life in rat plasma of compound 24 was prolonged after optimization, which would be helpful for increasing in vivo activities of this series of derivatives. All the studies confirmed that piperidine-containing non-covalent proteasome inhibitors can be potential leads for anti-MM drug development.
设计、合成并评价了一系列具有不同取代基的非共价哌啶肽衍生物作为蛋白酶体抑制剂。对所有合成的目标化合物进行蛋白酶体抑制评价后，选择了一些具有抗增殖活性的化合物进行了对三种多发性骨髓瘤（MM）细胞系的活性测试。8 个类似物的活性比卡非佐米更强，其中最有前途的化合物 24 对 20S 蛋白酶体的 IC 值为 0.8±0.2 nM，对 RPMI 8226、NCI-H929 和 MM.1S 细胞系的抑制活性分别为 8.42±0.74 nM、7.14±0.52 nM 和 14.20±1.08 nM。此外，还进一步研究了代表性化合物 24 的抗癌活性机制。通过积累多聚泛素和诱导半胱天冬酶和 PARP 的裂解，使 RPMI-8226 细胞发生凋亡。此外，化合物 24 在大鼠血浆中的半衰期经优化后延长，这有助于提高该系列衍生物的体内活性。所有研究都证实，含有哌啶的非共价蛋白酶体抑制剂可能成为抗 MM 药物开发的潜在先导化合物。
