Inhibition of Protein Kinase Cα 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 Cα (PKCα). In vitro assays of monomeric and dimeric analogues support a model in which DECA inhibits PKCα by an obligatory two-point contact, a unique mechanism among PKC inhibitors. The presence of unsaturation in the center of the C10-alkyl linker produced geometric isomers with different inhibitory potencies: cis IC50 = 52 ± 12 μM and trans IC50 = 12 ± 3 μM, where the trans isomer was equipotent to that of the saturated C10-DECA. DECA analogues with longer, saturated linkers (C12, C14, or C16) exhibited enhanced inhibitory potencies which reached a plateau with the C14-linker (IC50 = 2.6 ± 0.2 μM). Metastatic melanoma cells treated with 250 nM C12-, C14-, or C16-DECA and irradiated with long-wave UV light (which causes irreversible inhibition of PKCα by DECA) confirmed the linker-dependent inhibition of intracellular PKCα activity.