Discovery of novel AHLs as potent antiproliferative agents

• Three series of novel AHLs were synthesized and evaluated for their cytotoxicity.
• Some of these AHLs showed better cytotoxicity than 5-Fu and OdDHL.
• 4-Amino chalcone scaffold was first discovered with promising cytotoxicity.
• Compound 11e was found to be able to induce apoptosis of MCF-7 cells.
• Compound 11e arrested cell cycle of MCF-7 cells at G2/M phase.

Three series of novel AHL analogs were synthesized and evaluated for their in vitro cytotoxic activity against four human cancer cell lines. The SARs investigation indicated that AHLs with a terminal phenyl group, especially those with the chalcone scaffold had remarkably enhanced cytotoxicity than those with the hydrophobic side chains. Besides, some of these compounds were much more potent than 5-Fu and natural OdDHL. Through the detailed SARs discussions, we found that compounds 10a-k and 14 with the 4-amino chalcone scaffold showed excellent inhibition against all the tested cancer cell lines and were much more potent than 5-Fu and AHLs. Such scaffold may act as a template for further lead optimization. Compound 10i with a 3, 4, 5-trimethoxy group was the most potent one against all the tested cancer cell lines. Flow cytometry analysis indicated that analog 11e induced the cellular apoptosis and cell cycle arrest of MCF-7 cells at G2/M phase in a concentration-and time-dependent manner.

Extensive SARs studies of AHLs have led to the identification of compound 11e with potent cytotoxicity, which can induce the cellular apoptosis and cell cycle arrest of MCF-7 cells at G2/M phase in a concentration-and time-dependent manner.Figure optionsDownload as PowerPoint slide