- Title
- 5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors
- Creator
- Robertson, Mark J.; Horatscheck, André; Haucke, Volker; McCluskey, Adam; Sauer, Samantha; von Kleist, Lisa; Baker, Jennifer R.; Stahlschmidt, Wiebke; Nazaré, Marc; Whiting, Ainslie; Chau, Ngoc; Robinson, Phillip J.
- Relation
- Organic & Biomolecular Chemistry Vol. 14, Issue 47, p. 11266-11278
- Publisher Link
- http://dx.doi.org/10.1039/c6ob02308h
- Publisher
- Royal Society of Chemistry
- Resource Type
- journal article
- Date
- 2016
- Description
- 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.
- Subject
- clathrin inhibitors; endocytosis; mitosis
- Identifier
- http://hdl.handle.net/1959.13/1340419
- Identifier
- uon:28474
- Identifier
- ISSN:1477-0520
- Language
- eng
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