- Title
- Development of second-generation indole-based dynamin GTPase inhibitors
- Creator
- Gordon, Christopher P.; Venn-Brown, Barbara; Robertson, Mark J.; Young, Kelly A.; Chau, Ngoc; Mariana, Anna; Whiting, Ainslie; Chircop, Megan; Robinson, Phillip J.; McCluskey, Adam
- Relation
- NHMRC
- Relation
- Journal of Medicinal Chemistry Vol. 56, Issue 1, p. 46-59
- Publisher Link
- http://dx.doi.org/10.1021/jm300844m
- Publisher
- American Chemical Society
- Resource Type
- journal article
- Date
- 2013
- Description
- 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, IC50(dyn I) = 7.7 μM), reduced under flow chemistry conditions (20, IC50(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 (IC50 (dyn I) = 0.56 μM) and 25 (IC50(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 (IC50(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.
- Subject
- dynamin GTPase; endocytic pathways; indole 24; clathrin-mediated endocytosis
- Identifier
- http://hdl.handle.net/1959.13/1300823
- Identifier
- uon:20159
- Identifier
- ISSN:0022-2623
- Language
- eng
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