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

[Display omitted] 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.