The motuporamines are natural products isolated from the New Guinea sea sponge Xestospongia exigua. Dihydromotuporamine C contains a large macrocycle and an appended polyamine component and was shown to be both antimetastatic and cytotoxic to human L3.6pl pancreatic cancer cells. A series of macrocycle-polyamine conjugates were prepared, and the sequence of the polyamine component was varied to optimize the antimigration properties (as measured in L3.6pl cells) of this molecular class. A one-carbon spacer between the 15-membered carbocycle and the appended polyamine showed improved antimigration properties. A survey of different polyamine sequences containing two, three, or four carbon spacers revealed that the natural polyamine sequence (norspermidine, a 3,3-triamine) was superior in terms of inhibiting the migration of L3.6pl cells in vitro. An investigation of the respective ceramide and sphingomyelin populations in L3.6pl cells revealed that these molecules can modulate both ceramide and sphingomyelin pools in cells and inhibit cell migration.