Symbolic Structures on Corner Manifolds

Abstract

The Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway controls multiple biological processes, including cell survival, proliferation, and differentiation. Abnormally activated STAT3 signaling promotes tumor cell growth, proliferation, and survival, as well as tumor invasion, angiogenesis, and immunosuppression. Hence, JAK/STAT3 signaling has been considered a promising target for antitumor therapy. In this study, a number of ageladine A derivative compounds were synthesized. The most effective of these was found to be compound <b>25</b>. Our results indicated that compound <b>25</b> had the greatest inhibitory effect on the STAT3 luciferase gene reporter. Molecular docking results showed that compound <b>25</b> could dock into the STAT3 SH2 structural domain. Western blot assays demonstrated that compound <b>25</b> selectively inhibited the phosphorylation of STAT3 on the Tyr705 residue, thereby reducing STAT3 downstream gene expression without affecting the expression of the upstream proteins, p-STAT1 and p-STAT5. Compound <b>25</b> also suppressed the proliferation and migration of A549 and DU145 cells. Finally, in vivo research revealed that 10 mg/kg of compound <b>25</b> effectively inhibited the growth of A549 xenograft tumors with persistent STAT3 activation without causing significant weight loss. These results clearly indicate that compound <b>25</b> could be a potential antitumor agent by inhibiting STAT3 activation.