title: 5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors.
abstract: The development of a (Z)-5-((6,8-dichloro-4-oxo-4H-chromen-3-yl)methylene)-2-thioxothiazolidin-4-one (2), rhodanine-based lead that led to the Pitstop® 2 family of clathrin inhibitors is described herein. Head group substitution and bioisosteric replacement of the rhodanine core with a 2-aminothiazol-4(5H)-one scaffold eliminated off target dynamin activity. A series of N-substituents gave first phenylglycine (20, IC50∼ 20 μM) then phenyl (25, IC50∼ 7.1 μM) and 1-napthyl sulfonamide (26, Pitstop® 2 compound, IC50∼ 1.9 μM) analogues with good activity, validating this approach. A final library exploring the head group resulted in three analogues displaying either slight improvements or comparable activity (33, 38, and 29 with IC50∼ 1.4, 1.6 and 1.8 μM respectively) and nine others with IC50< 10 μM. These results were rationalized using in silico docking studies. Docking studies predicted enhanced Pitstop® 2 family binding, not a loss of binding, within the Pistop® groove of the reported clathrin mutant invalidating recent assumptions of poor selectivity for this family of clathrin inhibitors.
authors.affiliation: Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Robertson
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Horatscheck
authors.affiliation: Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Samantha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: von Kleist
authors.affiliation: Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Baker
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Stahlschmidt
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Nazaré
authors.affiliation: Cell Signaling Unit, Children's Medical Research Institute, The University of Sydney, Sydney, NSW 2145, Australia.
authors.forename: Ainslie
authors.initials: A
authors.lastname: Whiting
authors.affiliation: Cell Signaling Unit, Children's Medical Research Institute, The University of Sydney, Sydney, NSW 2145, Australia.
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.affiliation: Cell Signaling Unit, Children's Medical Research Institute, The University of Sydney, Sydney, NSW 2145, Australia.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
authors.affiliation: Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D002966:Clathrin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002966:Clathrin; D013449:Sulfonamides