Synthesis and antiproliferative activity of indolizine derivatives incorporating a cyclopropylcarbonyl group against Hep-G2 cancer cell line

Indolizine and annulated indolizine derivatives incorporating a cyclopropylcarbonyl group were synthesized in a one pot procedure by the tanden reactions of [3 + 2] cycloaddition of the corresponding N-ylide with electron deficient alkene. Seventeen indolizine derivatives were reported for the first time. All the compounds were examined for their antiproliferative activity against the human hepatocellular liver carcinoma (Hep-G2) cell line by MTT method. Among the compounds tested, 5a, 5d, 5g and 5j showed the most favorable activities with IC50 values of 0.39, 0.48, 0.29 and 0.20 μg/mL. Especially, compound 5j displayed potent antiproliferative activities with IC50 value of 0.20 μg/mL, and showed significant EGFR kinase inhibitory activity with IC50 value of 0.085 μM. Docking simulations of 5j were carried out to illustrate the binding mode of the molecular into the EGFR active site.

Graphical abstractIndolizine and annulated indolizine derivatives incorporating a cyclopropylcarbonyl group were synthesized by the tanden reactions of [3 + 2] cycloaddition of the corresponding N-ylide with electron deficient alkene.Figure optionsDownload full-size imageDownload as PowerPoint slide