Synthesis of Dynole 34-2, Dynole 2-24 and Dyngo 4a for investigating dynamin GTPase

Nat Protoc. 2014 Apr;9(4):851-70. doi: 10.1038/nprot.2014.046. Epub 2014 Mar 20.

Abstract

Dynamin is a large GTPase with roles in membrane fission during clathrin-mediated endocytosis, in actin dynamics and in cytokinesis. Defects in dynamin have been linked to human diseases. The synthesis of a dynamin modulator toolkit comprising two different inhibitor classes is described. The first series comprises Dynole 34-2, Dynole 2-24 and the inactive control Dynole 31-2. The Dynole compounds act on the dynamin G domain, are not GTP competitive and can be synthesized in 2-3 d. Knoevenagel condensation of 1-(3-(dimethylamino)propyl)-1H-indole-3-carbaldehyde (1) with cyanoamides (2 and 3) affords Dynole 31-2 and Dynole 34-2, respectively. Reductive amination of 1 with decylamine gives Dynole 2-24. The second series acts at an allosteric site in the G domain of dynamin and comprises Dyngo 4a and Dyngo Ø (inactive control). Both are synthesized in an overnight reaction via condensation of 3-hydroxy-2-naphthoic hydrazide with 2,4,5-trihydroxybenzaldehyde to afford Dyngo 4a, or with benzaldehyde to afford Dyngo Ø.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Chemistry Techniques, Synthetic
  • Cyanoacrylates / chemical synthesis*
  • Dynamins / chemistry*
  • Hydrazones / chemical synthesis*
  • Indoles / chemical synthesis*
  • Naphthols / chemical synthesis*

Substances

  • Cyanoacrylates
  • Hydrazones
  • Indoles
  • N-((1-(3-(dimethylamino)propyl)-1H-indol-3-yl)methyl)decan-1-amine
  • Naphthols
  • dyngo-4a
  • dynole 34-2
  • Dynamins