Poly (ADP-ribose) polymerase (PARP) inhibitors have been authorized for the treatment of breast cancer (BC) and prostate cancer (PC). Recent studies suggest that inhibiting angiogenesis through the vascular endothelial growth factor receptor (VEGFR) enhances cellular sensitivity to PARP inhibitors. This study presents the design, synthesis and full characterization of dual VEGFR-2 and PARP-1 inhibitors obtained by conjugating a PARP-1 inhibitor with VEGFR-2 inhibitor fragments (indole, benzofuran, and piperazine). Four compounds exhibited significant inhibitory activities against human prostate cancer cell lines (PC3) and breast cancer cell lines (MCF7) at 48 h. These compounds were identified as dual VEGFR-2 and PARP-1 inhibitors with low or sub-micromolar ranges, especially 12f, with IC50 values of 0.43 μM and 1.10 μM, respectively. Moreover, the potent compound 12f markedly decreased scratch wound closure and colony formation. Moreover, compound 12f significantly induced apoptosis in PC3 cells and arrested cells at the S phase. The dual inhibition of VEGFR-2 and PARP-1 protein kinase was further validated using western blotting. Applying molecular docking and dynamics determined the target compound's binding mechanism.
Novel benzofuran-conjugated indolin-2-ones as anticancer agents; design, synthesis, biological assessments, and molecular modeling insights
di Giacomo, Viviana;Balaha, Marwa
2025-01-01
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors have been authorized for the treatment of breast cancer (BC) and prostate cancer (PC). Recent studies suggest that inhibiting angiogenesis through the vascular endothelial growth factor receptor (VEGFR) enhances cellular sensitivity to PARP inhibitors. This study presents the design, synthesis and full characterization of dual VEGFR-2 and PARP-1 inhibitors obtained by conjugating a PARP-1 inhibitor with VEGFR-2 inhibitor fragments (indole, benzofuran, and piperazine). Four compounds exhibited significant inhibitory activities against human prostate cancer cell lines (PC3) and breast cancer cell lines (MCF7) at 48 h. These compounds were identified as dual VEGFR-2 and PARP-1 inhibitors with low or sub-micromolar ranges, especially 12f, with IC50 values of 0.43 μM and 1.10 μM, respectively. Moreover, the potent compound 12f markedly decreased scratch wound closure and colony formation. Moreover, compound 12f significantly induced apoptosis in PC3 cells and arrested cells at the S phase. The dual inhibition of VEGFR-2 and PARP-1 protein kinase was further validated using western blotting. Applying molecular docking and dynamics determined the target compound's binding mechanism.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
