Synthesis of Anti-Pancreatic Cancer Natural Product Majusculamide D and Analogues Reveals a Preliminary Structure-Activity Relationships

The total synthesis of majusculamide D (1) was achieved from commercially available materials. In addition, we synthesized eight analogues including three stereoisomers of majusculamide D that differ in the fatty acid chain. Six analogues including a simplified analogue 29 exhibited significant nanomolar-level IC50 values against Panc-1 cells in MTT assays. A preliminary SAR analysis indicated that the hydroxyl group at C10 and C2-C3 unsaturated double bond of majusculamide D were essential in maintaining the high activity against Panc-1 cells and the orientation of C40-Me and C42-Me groups was tolerable.