2. Academic Validation
  3. Novel aromatic sulfonyl naphthalene-based boronates as 20S proteasome inhibitors

Novel aromatic sulfonyl naphthalene-based boronates as 20S proteasome inhibitors

  • Bioorg Med Chem. 2018 Mar 1;26(5):1050-1061. doi: 10.1016/j.bmc.2018.01.017.
Hongwu Liu 1,  Jianwei Wu 1,  Ying Ge 1,  Aibo Li 1,  Jia Li 1,  Zhengshi Liu 1,  Yungen Xu 2,  Qingxiang Xu 3,  Yuyan Li 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Nanjing 210008, China.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yuyanli@cpu.edu.cn.
PMID: 29426629 DOI: 10.1016/j.bmc.2018.01.017
Abstract

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 (IC50 = 6.942 μM, MCF-7) and 2c (IC50 = 6.905 μM, MCF-7) displayed higher anti-proliferative activities than Bortezomib (IC50 = 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.

Keywords

20S proteasome inhibitors; Bortezomib; Metabolic stability; Non-peptide scaffold.

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