Design, synthesis, and biological evaluation of novel (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives as potent STAT3-targeting anticolorectal cancer agents.

Dysregulation of signal transducer and activator of transcription 3 (STAT3) is implicated in the pathogenesis of various cancers, underscoring its potential as a cancer therapeutic target. In this work, we designed and synthesized a novel series of (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives and evaluated their anti-proliferative effects on tumour cells. Among these derivatives, NW16 exhibited remarkable antiproliferative activity against HCT116 cells, with an IC₅₀ value of 0.28 μM, and exhibited dose- and time-dependent inhibition of the JAK/STAT3 signalling pathway. In addition, NW16 induced reactive oxygen species (ROS) production, which subsequently suppressed the ROS-dependent PI3K/AKT pathway and enhanced its antitumour efficacy. In vivo studies confirmed significant tumour-suppressive effects upon oral administration of NW16 along with favourable tolerability in a colorectal cancer xenograft model. These results indicate that NW16 could be a promising candidate for developing targeted therapy for colorectal cancer because of its multifaceted mechanism.