Unforeseen Possibilities To Investigate the Regulation of Polyamine Metabolism Revealed by Novel C‑Methylated Spermine Derivatives

The biogenic polyamines, spermine (Spm) and spermidine,
are organic
polycations present in millimolar concentrations in all eukaryotic
cells participating in the regulation of vital cellular functions
including proliferation and differentiation. The design and biochemical
evaluation of polyamine analogues are cornerstones of polyamine research.
Here we synthesized and studied novel C-methylated Spm analogues:
2,11-dimethylspermine (2,11-Me2Spm), 3,10-dimethylspermine
(3,10-Me2Spm), 2-methylspermine, and 2,2-dimethylspermine.
The tested analogues overcame growth arrest induced by a 72 h treatment
with α-difluoromethylornithine, an ornithine decarboxylase (ODC)
inhibitor, and entered into DU145 cells via the polyamine transporter.
3,10-Me2Spm was a poor substrate of spermine oxidase and
spermidine/spermine-N1-acetyltransferase
(SSAT) when compared with 2,11-Me2Spm, thus resembling
1,12-dimethylspermine, which lacks the substrate properties required
for the SSAT reaction. The antizyme (OAZ1)-mediated downregulation
of ODC and inhibition of polyamine transport are crucial in the maintenance
of polyamine homeostasis. Interestingly, 3,10-Me2Spm was
found to be the first Spm analogue that did not induce OAZ1 and, consequently,
was a weak downregulator of ODC activity in DU145 cells.