title: Inhibition of protein kinase C(alpha) by dequalinium analogues: dependence on linker length and geometry.
abstract: 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 dimeric analogues support a model in which DECA inhibits PKC(alpha) 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 microM and trans IC(50) = 12 +/- 3 microM, 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 microM). 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 PKC(alpha) by DECA) confirmed the linker-dependent inhibition of intracellular PKC(alpha) activity.
authors.affiliation: Department of Chemistry and Biochemistry, Graduate School and University Center, and Queens College of The City University of New York, Flushing, New York 11367, USA.
authors.forename: D
authors.initials: D
authors.lastname: Qin
authors.forename: R
authors.initials: R
authors.lastname: Sullivan
authors.forename: W F
authors.initials: WF
authors.lastname: Berkowitz
authors.forename: R
authors.initials: R
authors.lastname: Bittman
authors.forename: S A
authors.initials: SA
authors.lastname: Rotenberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003868:Dequalinium / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D008968:Molecular Conformation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051571:Protein Kinase C-alpha; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D003868:Dequalinium; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha