The Rhodadyns, a New Class of Small Molecule Inhibitors of Dynamin GTPase Activity

  • ACS Med Chem Lett. 2012 Mar 26;3(5):352-6. doi: 10.1021/ml200284s.
Mark J Robertson  1 ,  Gordana Hadzic  1 ,  Joseph Ambrus  1 ,  D Yuri Pomè  1 ,  Emily Hyde  1 ,  Ainslie Whiting  2 ,  Anna Mariana  2 ,  Lisa von Kleist  3 ,  Ngoc Chau  2 ,  Volker Haucke  3 ,  Phillip J Robinson  2 ,  Adam McCluskey  1
Affiliations
  • 1. Chemistry, The University of Newcastle , University Drive, Callaghan, NSW 2308, Australia.
  • 2. Cell Signalling Unit, Children's Medical Research Institute, The University of Sydney , Sydney, NSW 2145, Australia.
  • 3. Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin , 13125 Berlin, Germany.
PMID: 24900478 DOI: 10.1021/ml200284s
Abstract

Six focused rhodanine-based libraries, 60 compounds in total, were synthesized and evaluated as potential Dynamin I GTPase inhibitors. Twenty-six were more potent than the lead compound with 13 returning IC50 values ≤10 μM, making the Rhodadyn series among the most active Dynamin inhibitors reported. Two analogues were highly effective at blocking receptor-mediated endocytosis: C10 and D10 with IC50(RME) = 7.0 ± 2.2 and 5.9 ± 1.0 μM, respectively. These compounds are equipotent with the best reported in-cell Dynamin inhibitors.

Keywords
Knoevengal condensation; dynamin inhibition; rhodanine.
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