Unveiling the potential of isatin-grafted phenyl-1,2,3-triazole derivatives as dual VEGFR-2/STAT-3 inhibitors: Design, synthesis and biological assessments

Abstract

The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives “6a-n” and “9a-f”. Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC50 range 53–82 nM, respectively) and STAT-3 (with IC50 range 5.63–10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.