Synthesis of α-fluorocinnamate derivatives as novel cathepsin S inhibitors with in vitro antiproliferative activity against pancreatic cancer cells

Cathepsins, key members of the papain-like family of cysteine proteases, are crucial for proteolysis processes within human cells, including osteolysis, immunomodulation and apoptosis. Recent research has highlighted the significant role of cathepsins, particularly the L, S, K, and B subtypes, in pancreatic cancer. This has driven the development of novel cathepsin inhibitors as potential treatments to inhibit tumor progression, migration and invasion. Targeting cathepsin S (CatS) has shown promise in reducing tumor progression and enhancing the efficacy of chemotherapeutic agents in preclinical models. Building on our previous work where we employed ethyl p-aminocinnamate ester derivatives for covalent inhibition of cysteine proteases, herein we have designed and synthesized three new derivatives basing on an isosteric replacement (H–F) at the level of cinnamate moiety. These derivatives emerged as potent covalent inhibitors of CatS (1.8–2.6 µM) with 2F showing also weak inhibition activity against CatL (20 %) and CatB (29 %). In vitro assays of 2F against pancreatic cancer cell lines BXPC3 and CAPAN1 revealed significant antiproliferative activity, with IC₅₀ = 5.79 µM and 20.75 µM, respectively. These findings underscore the potential of α-fluorocinnamate-based cysteine protease inhibitors as promising candidates for further development in targeting CatS and CatL with the aim to reduce pancreatic cancer cell proliferation.