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
  • 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: [email protected].
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.