DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL INDOLE-CONTAINING SORAFENIB DERIVATIVES

Based on the molecular structure of sorafenib, a series of novel indole (ketone) semicarbazide analogs (1-30) have been designed and synthesized. All new compounds were identified by H-1, C-13 NMR and FIRMS, and their antiproliferative activity on four cancer cell lines A549, PC-3, K562 and HepG2 were evaluated. In particular, compared with the positive control sorafenib (18.92 mu mol/L), compounds 4, 6 and 20 showed two- to three-fold improvement in inhibiting the proliferation of PC-3 cells with IC50 values of 6.75, 8.03 and 8.77 mu mol/L respectively. In vitro activity evaluation experiments showed that compound 6 could significantly inhibit the proliferation and colony formation of PC-3 cells, induce apoptosis and arrest the cells in the G2/M phase. Finally, western blot speculated that compound 6 may affect the signal transduction of downstream signaling pathway PI3K/Akt by affecting EGFR protein and autophosphorylation thereby promoting cell apoptosis and inhibiting cell growth. These results provide important information for the development of new anti-cancer drugs.