School of Pharmacy, Fudan University, Shanghai 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Bioorg Chem. 2023 Sep;138:106626. doi: 10.1016/j.bioorg.2023.106626. Epub 2023 May 27.
Peptides have limitations as active pharmaceutical agents due to rapid hydrolysis by proteases and poor cell permeability. To overcome these limitations, a series of peptidyl proteasome inhibitors embedded with four-membered heterocycles were designed to enhance their metabolic stabilities. All synthesized compounds were screened for their inhibitory activities against human 20S proteasome, and 12 target compounds displayed potent efficacy with IC values lower than 20 nM. Additionally, these compounds exhibited strong anti-proliferative activities against multiple myeloma (MM) cell lines (MM1S: 72, IC = 4.86 ± 1.34 nM; RPMI-8226: 67, IC = 12.32 ± 1.44). Metabolic stability assessments of SGF, SIF, plasma and blood were conducted, and the representative compound 73 revealed long half-lives (Plasma: T = 533 min; Blood: T > 1000 min) and good proteasome inhibitory activity in vivo. These results suggest that compound 73 serve as a lead compound for the development of more novel proteasome inhibitors.
肽类由于蛋白酶的快速水解和较差的细胞通透性，作为活性药物制剂有其局限性。为了克服这些限制，设计了一系列嵌入四元杂环的肽蛋白酶体抑制剂，以提高它们的代谢稳定性。所有合成的化合物都对人 20S 蛋白酶体的抑制活性进行了筛选，有 12 个目标化合物表现出很强的功效，IC 值低于 20 nM。此外，这些化合物对多发性骨髓瘤（MM）细胞系（MM1S：72，IC=4.86±1.34 nM；RPMI-8226：67，IC=12.32±1.44）表现出很强的抗增殖活性。对 SGF、SIF、血浆和血液进行了代谢稳定性评估，代表性化合物 73 显示出长半衰期（血浆：T=533 分钟；血液：T>1000 分钟）和良好的体内蛋白酶体抑制活性。这些结果表明，化合物 73 可作为开发更新型蛋白酶体抑制剂的先导化合物。
