title: Development of second-generation indole-based dynamin GTPase inhibitors.
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.
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gordon
authors.forename: Barbara
authors.initials: B
authors.lastname: Venn-Brown
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Young
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.forename: Anna
authors.initials: A
authors.lastname: Mariana
authors.forename: Ainslie
authors.initials: A
authors.lastname: Whiting
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; D001921:Brain / Q000201:enzymology; D045744:Cell Line, Tumor; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D034285:Dynamin II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004705:Endocytosis; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012756:Sheep; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: C579721:2-cyano-3-(1-(3-(dimethylamino)propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide; D000178:Acrylamides; D007211:Indoles; C579722:N-((1-(3-(dimethylamino)propyl)-1H-indol-3-yl)methyl)decan-1-amine; C579723:N-((1-(3-(dimethylamino)propyl)-1H-indol-3-yl)methyl)dodecan-1-amine; D054852:Small Molecule Libraries; D034284:Dynamin I; D034285:Dynamin II