Inhibition of protein kinase C alpha by dequalinium analogues: Dependence on linker length and geometry

Analogues of a bipartite compound, dequalinium (DECA) (quinolinium, 1,1'-(1 ,10-decanediyl)bis(4-amino-2-methyl diiodide)), were tested for inhibition of protein kinase C alpha (PKC alpha). In vitro assays of monomeric and dim eric analogues support a model in which DECA inhibits PKC alpha by an oblig atory two-point contact, a unique mechanism among PKC inhibitors. The prese nce of unsaturation in the center of the C-10-alkyl linker produced geometr ic isomers with different inhibitory potencies: cis IC50 = 52 +/- 12 mu M a nd trans IC50 = 12 +/- 3 mu M, where the trans isomer was equipotent to tha t of the saturated C-10-DECA. DECA analogues with longer, saturated linkers (C-12, C-14, or C-16) exhibited enhanced inhibitory potencies which reache d a plateau with the C-14-linker (IC50 = 2.6 +/- 0.2 mu M) Metastatic melan oma cells treated with 250 nM C-12-, C-14-, or C-16-DECA and irradiated wit h long-wave UV light (which causes irreversible inhibition of PKC alpha by DECA) confirmed the linker-dependent inhibition of intracellular PKC alpha activity.