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Your search keyword '"Barbara Venn-Brown"' showing total 3 results
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3 results on '"Barbara Venn-Brown"'

1. Inhibition of Dynamin Mediated Endocytosis by the Dynoles—Synthesis and Functional Activity of a Family of Indoles

Author

Christopher P. Gordon, Megan Chircop, Andrew B. McGeachie, Timothy A. Hill, Annie Quan, Adam McCluskey, Jennette A. Sakoff, Anna Mariana, Phillip J. Robinson, Luke R. Odell, Barbara Venn-Brown, and Ngoc Chau

Subjects
Indoles, Tertiary amine, Cell Survival, media_common.quotation_subject, Drug Evaluation, Preclinical, GTPase, Endocytosis, Cell Line, Small Molecule Libraries, Mice, Structure-Activity Relationship, Drug Discovery, Animals, Humans, Enzyme Inhibitors, Internalization, Dynamin I, Dynamin, media_common, Acrylamides, Dose-Response Relationship, Drug, Molecular Structure, biology, Chemistry, Stereoisomerism, Receptor-mediated endocytosis, Cell biology, Biochemistry, Enzyme inhibitor, NIH 3T3 Cells, biology.protein, Molecular Medicine, Uncompetitive inhibitor
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.

Published
2009

2. Development of second-generation indole-based dynamin GTPase inhibitors

Author

Phillip J. Robinson, Barbara Venn-Brown, Ngoc Chau, Ainslie Whiting, Adam McCluskey, Mark J. Robertson, Christopher P. Gordon, Anna Mariana, Megan Chircop, and Kelly A. Young

Subjects
Indole test, Acrylamides, Indoles, Sheep, Isostere, Stereochemistry, Chemistry, Brain, Endocytosis, Reductive amination, Small Molecule Libraries, Dynamin II, Structure-Activity Relationship, Cell Line, Tumor, Drug Discovery, Molecular Medicine, Moiety, Animals, Humans, Amine gas treating, Selectivity, Dynamin I, Dynamin
Abstract

Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino)propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide (2) confirmed the tertiary dimethylamino-propyl moiety as critical for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced with a thiazole-4(5H)-one isostere (19, IC(₅₀(dyn I)) = 7.7 μM), reduced under flow chemistry conditions (20, IC(₅₀(dyn I)) = 5.2 μM) or replaced by a simple amine. The latter provided a basis for a high yield library of compounds via a reductive amination by flow hydrogenation. Two compounds, 24 (IC(₅₀ (dyn I)) = 0.56 μM) and 25 (IC(₅₀(dyn I)) = 0.76 μM), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC(₅₀(CME)) = 1.9 μM). It also showed 4.4-fold selectivity for dynamin I. The indole 24 compound has improved isoform selectivity and is the most active in-cell inhibitor of clathrin-mediated endocytosis reported to date.

Published
2012

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