Total synthesis of Litcubanine A and comparative anti-inflammatory activity assessment of its derivatives

Litcubanine A (LA), an isoquinoline alkaloid characterized by a specific C-1 methyl group and an N → O moiety, exhibits significant anti-inflammatory activity, suggesting its potential as a lead compound for the development of novel macrophage-targeted anti-inflammatory drugs. However, the low natural abundance of LA in plants poses challenges for extraction and isolation to meet the demands of subsequent drug development. To overcome this limitation, we developed a concise and efficient total synthesis strategy. Utilizing a classical Bischler-Napieralski cyclization followed by the N-oxidation reaction, the synthesis of LA was accomplished in only four steps, providing multigram quantities of the target compound with an overall yield of 21.7%. The anti-inflammatory activity of LA, along with those of key synthetic intermediates and structural analogues, we subsequently evaluated.