Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Oncology

Background:

• Esophageal squamous cell carcinoma (ESCC) presents a significant global health challenge due to its high mortality rate.
• Existing treatments for ESCC often have limitations, necessitating the development of novel therapeutic agents.
• Indoline scaffolds have emerged as promising structures for designing effective anticancer compounds.

Purpose of the Study:

• To design, synthesize, and evaluate novel indoline derivatives for their potential anticancer properties.
• To identify specific indoline derivatives with potent antiproliferative activity against ESCC cell lines.
• To elucidate the mechanism of action of the most active compounds, particularly their interaction with tubulin.

Main Methods:

• Synthesis of a series of indoline derivatives.
• In vitro antiproliferative assays using various human cancer cell lines (MGC-803, A549, Kyse30, Kyse450, Kyse510, EC-109).
• Tubulin polymerization inhibition assays, molecular docking studies, and cell growth inhibition assays.

Main Results:

• Compound 9d demonstrated significant antiproliferative activity across multiple cell lines, with IC50 values as low as 1.49 μM.
• Compound 9d was identified as a tubulin inhibitor targeting the colchicine binding site, with an IC50 of 3.4 μM.
• Molecular docking confirmed the binding of compound 9d to the colchicine binding site of tubulin, and it suppressed tubulin polymerization in Kyse450 cells.

Conclusions:

• Indoline derivatives represent a promising class of novel tubulin inhibitors with significant potential for anticancer drug development.
• Compound 9d exhibits potent anticancer activity and a well-defined mechanism of action, warranting further investigation for ESCC therapy.
• The findings support the continued exploration of indoline-based compounds as a strategy for developing new treatments for esophageal cancer.