Synthesis of the novel (±)-2-methoxy-6-icosynoic acid—A fatty acid that induces death of neuroblastoma cells

• The α-methoxy functionality enhances the cytotoxicity of fatty acids toward in vitro models of neuroblastoma.
• The α-methoxylated acetylenic fatty acids form micelles more readily than their nonmethoxylated ones.
• These results provide insights into strategies whereby the α-methoxylated fatty acids could be used in micelles to transport drugs in the fight against cancer.

The first total synthesis for the novel fatty acid (±)-2-methoxy-6-icosynoic acid was accomplished in seven steps and in a 14% overall yield starting from 2-(4-bromobutoxy)-tetrahydro-2H-pyran. The title compound displayed an EC50 = 23 ± 1 μM against the human SH-SY5Y neuroblastoma cell line and an EC50 = 26 ± 1 μM against the human adenocarcinoma cervix cell line (HeLa) after 48 h of exposure. The corresponding non-methoxylated analog 6-icosynoic acid did not display cytotoxicity (EC50 > 500 μM) toward the studied cell lines as well as the 2-methoxyicosanoic acid (EC50 > 300 μM). The critical micelle concentration (CMC = 20–30 μM) for the (±)-2-methoxy-6-icosynoic acid was also determined. It was found that α-methoxylation decreases the CMC of a fatty acid.