Synthesis and Bioevaluation of Macrocycle–Polyamine Conjugates as Cell Migration Inhibitors

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.