Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem. 2018 Mar 1;26(5):1050-1061. doi: 10.1016/j.bmc.2018.01.017. Epub 2018 Feb 6.
A novel series of non-peptide proteasome inhibitors (PIs) that act on chymotrypsin-like (ChT-L) of the proteasome were developed. These PIs bearing 4-aromatic sulfonyl naphthalene-based scaffold and Leu-boronic moiety as covalent bonding group displayed far better activity than PI-8182 for inhibiting ChT-L in preliminary biological activity test. The results showed that 2a (IC = 6.942 μM, MCF-7) and 2c (IC = 6.905 μM, MCF-7) displayed higher anti-proliferative activities than Bortezomib (IC = 18.37 μM, MCF-7) under our experimental conditions. Furthermore, in the microsomal stability assay, 2a demonstrated excellent metabolic stability profiles with 56% remaining after 40 min, as compared to Bortezomib of which approximately 30% was remaining. The compounds 2a, 2c emerged as promising lead compounds for the development of novel non-peptide boronate PIs.
开发了一系列新型非肽蛋白酶体抑制剂（PI），作用于蛋白酶体的糜蛋白酶样（ChT-L）。在初步的生物活性测试中，这些带有 4-芳基磺酰基萘基骨架和亮氨酰硼酸部分作为共价键合基团的 PI 显示出比 PI-8182 更强的抑制 ChT-L 的活性。结果表明，在我们的实验条件下，化合物 2a（IC = 6.942 μM，MCF-7）和 2c（IC = 6.905 μM，MCF-7）的抗增殖活性均高于硼替佐米（IC = 18.37 μM，MCF-7）。此外，在微粒体稳定性测定中，化合物 2a 表现出优异的代谢稳定性，40 分钟后仍有 56%的药物残留，而硼替佐米的残留量约为 30%。化合物 2a 和 2c 有望成为新型非肽硼酸蛋白酶体抑制剂的有前途的先导化合物。
