title: N-methyl-substituted fluorescent DAG-indololactone isomers exhibit dramatic differences in membrane interactions and biological activity.
abstract: N-methyl-substituted diacylglycerol-indololactones (DAG-indololactones) are newly synthesized effectors of protein kinase C (PKC) isoforms and exhibit substantial selectivity between RasGRP3 and PKCα. We present a comprehensive analysis of membrane interactions and biological activities of several DAG-indololactones. Translocation and binding activity assays underline significant variations between the PKC translocation characteristics affected by the ligands as compared to their binding activities. In parallel, the fluorescent properties of the ligands were employed for analysis of their membrane association profiles. Specifically, we found that a slight change in the linkage to the indole ring resulted in significant differences in membrane binding and association of the DAG-indololactones with lipid bilayers. Our analysis shows that seemingly small structural modifications of the hydrophobic regions of these biomimetic PKC effectors contribute to pronounced modulation of membrane interactions of the ligands.
authors.affiliation: Department of Chemistry, Ben Gurion University, Beer Sheva 84105, Israel.
authors.forename: Noga
authors.initials: N
authors.lastname: Gal
authors.forename: Sofiya
authors.initials: S
authors.lastname: Kolusheva
authors.forename: Noemi
authors.initials: N
authors.lastname: Kedei
authors.forename: Andrea
authors.initials: A
authors.lastname: Telek
authors.forename: Taiyabah A
authors.initials: TA
authors.lastname: Naeem
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Langston
authors.initials: L
authors.lastname: Lim
authors.forename: Poonam
authors.initials: P
authors.lastname: Mannan
authors.forename: Susan H
authors.initials: SH
authors.lastname: Garfield
authors.forename: Saïd
authors.initials: S
authors.lastname: El Kazzouli
authors.forename: Dina M
authors.initials: DM
authors.lastname: Sigano
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004075:Diglycerides / Q000737:chemistry / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007536:Isomerism; D007783:Lactones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D007783:Lactones; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha