Design, synthesis, and biological evaluation of novel napabucasin-melatonin hybrids as potent STAT3 inhibitors

The current work developed diverse novel napabucasin-melatonin hybrids as potent STAT3 inhibitors. Several biological studies have suggested many compounds demonstrating potent inhibition against different tumor cells. Among these, compound 7e depicted enhanced inhibition against HepG2, MDA-MB-231, and A549 cells than napabucasin, with IC50 values of 1.06, 1.38, and 1.3 mu M, respectively. Based on fluorescence polarization analysis, compound 7e was bound to the SH2 domain in STAT3, with an IC50 value of 12.95 mu M. Molecular docking further confirmed the 7e binding mode inside the SH2 domain of STAT3. Further mechanistic studies indicated that 7e inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 down-stream genes (CyclinD1, Bcl-2 and c-Myc) instead of affecting p-STAT1 expression. Meanwhile, the phosphory-lation levels of its upstream kinases JAK2 and bypass kinase Erk1/2 remain unaffected. Simultaneously, 7e induced cancer cell apoptosis in a concentration-dependent manner. Significantly, 20 mg/kg (i.p.) compound 7e suppressed the mouse HepG2 xenograft development in vivo without body weight loss, suggesting that it could be an effective antitumor agent.

Automated summary

The current study developed various novel napabucasin-melatonin hybrids as potent STAT3 inhibitors. Multiple biological studies have shown that many compounds have strong inhibition against different tumor cells. Among them, compound 7e demonstrated enhanced inhibition against HepG2, MDA-MB-231, and A549 cells compared to napabucasin, with IC50 values of 1.06, 1.38, and 1.3 μM, respectively. The compound was found to bind to the SH2 domain in STAT3, inhibiting its activation and downstream gene expression, and inducing cancer cell apoptosis in a concentration-dependent manner. Moreover, in vivo experiments demonstrated that 20 mg/kg (i.p.) of compound 7e effectively suppressed the development of HepG2 xenografts in mice without causing weight loss, suggesting its potential as an antitumor agent.