Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/917531

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Title
Inhibition of dynamin mediated endocytosis by the dynoles-synthesis and functional activity of a family of indoles
Author/Creator
Hill, Timothy A.;  Gordon, Christopher P.;  Robinson, Phillip J.;  McCluskey, Adam;  McGeachie, Andrew B.;  Venn-Brown, Barbara;  Odell, Luke R.;  Chau, Ngoc;  Quan, Annie;  Mariana, Anna;  Sakoff, Jennette A.;  Chircop, Megan
Institution
The University of Newcastle. Faculty of Science & Information Technology, School of Environmental and Life Sciences
Description
Screening identified two bisindolylmaleimides as 100 μM 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 μM 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 (IC50 15 μM; RME IC50 80 μM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.
Relation
Journal of Medicinal Chemistry Vol. 52, Issue 12, p. 3762-3773
Publisher Link
http://dx.doi.org/10.1021/jm900036m
Date
2009
Publisher
American Chemical Society
Keyword(s)
synaptic vesicle endocytosis;  protein kinase C;  GTPase activity;  phosphorylation;  indolocarbazoles;  (-)-K252a;  aglycons
Resource Type
journal article
Identifier
http://hdl.handle.net/1959.13/917531
Identifier
ISSN:0022-2623
Reviewed
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Subject
"Journal of Medicinal Chemistry"
 
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