Design, Synthesis, and Selective Antiproliferative Activity of Indolizine Derivatives as Microtubule Destabilizers

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Developing selective anticancer agents with minimal toxicity is a key therapeutic challenge.
• Indolizine derivatives are explored for their potential biological activities.

Purpose of the Study:

• To synthesize and evaluate novel indolizine derivatives for anticancer properties.
• To identify potent and selective anticancer agents targeting specific cancer cell lines.

Main Methods:

• Synthesis of 32 indolizine derivatives.
• Antiproliferative assays against oral, breast, and gastric cancer cell lines, and normal fibroblasts.
• Cell-cycle analysis, tubulin polymerization inhibition assays, and Western blotting.
• Molecular docking studies to predict binding interactions.

Main Results:

• Compounds 8e and 8h demonstrated potent antiproliferative activity (nanomolar IC₅₀ values) and selectivity against cancer cells.
• These compounds induced G2/M cell-cycle arrest and inhibited tubulin polymerization.
• Modulation of apoptosis and proliferation-related proteins (p-AKT, cyclin D1, Bcl-2, p21) was observed.
• Docking studies confirmed binding to the colchicine-binding site of tubulin.

Conclusions:

• Indolizine derivatives 8e and 8h are promising selective anticancer agents.
• These compounds act as microtubule-interacting agents.
• Further investigation is warranted for their therapeutic potential in cancer treatment.