title: Inhibition of dynamin mediated endocytosis by the dynoles--synthesis and functional activity of a family of indoles.
abstract: Screening identified two bisindolylmaleimides as 100 microM inhibitors of the GTPase activity of dynamin I. Focused library approaches allowed development of indole-based dynamin inhibitors called dynoles. 100-Fold in vitro enhancement of potency was noted with the best inhibitor, 2-cyano-3-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-N-octylacrylamide (dynole 34-2), a 1.3 +/- 0.3 microM dynamin I inhibitor. Dynole 34-2 potently inhibited receptor mediated endocytosis (RME) internalization of Texas red-transferrin. The rank order of potency for a variety of dynole analogues on RME in U2OS cells matched their rank order for dynamin inhibition, suggesting that the mechanism of inhibition is via dynamin. Dynoles are the most active dynamin I inhibitors reported for in vitro or RME evaluations. Dynole 34-2 is 15-fold more active than dynasore against dynamin I and 6-fold more active against dynamin mediated RME (IC(50) approximately 15 microM; RME IC(50) approximately 80 microM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hill
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gordon
authors.forename: Andrew B
authors.initials: AB
authors.lastname: McGeachie
authors.forename: Barbara
authors.initials: B
authors.lastname: Venn-Brown
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.forename: Annie
authors.initials: A
authors.lastname: Quan
authors.forename: Anna
authors.initials: A
authors.lastname: Mariana
authors.forename: Jennette A
authors.initials: JA
authors.lastname: Sakoff
authors.forename: Megan
authors.initials: M
authors.lastname: Chircop
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C541935:2-cyano-N-octyl-3-(1-(3-dimethylaminopropyl)-1H-indol-3-yl)acrylamide; D000178:Acrylamides; D004791:Enzyme Inhibitors; D007211:Indoles; D054852:Small Molecule Libraries; D034284:Dynamin I