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 Ca (PKCa). In vitro assays of monomeric and dimeric analogues support a model in which DECA inhibits PKCa by an obligatory two-point contact, a unique mechanism among PKC inhibitors. The presence of unsaturation in the center of the C 10 -alkyl linker produced geometric isomers with different inhibitory potencies: cis IC 50 = 52 ± 12 μM and trans IC 50 = 12 ± 3 μM, where the trans isomer was equipotent to that of the saturated C 10 -DECA. DECA analogues with longer, saturated linkers (C 12 , C 14 , or C 16 ) exhibited enhanced inhibitory potencies which reached a plateau with the C 14 -linker (IC 50 = 2.6 ± 0.2 μM). Metastatic melanoma cells treated with 250 nM C 12 -, C 14 -, or C 16 -DECA and irradiated with long-wave UV light (which causes irreversible inhibition of PKCa by DECA) confirmed the linker-dependent inhibition of intracellular PKCa activity.