5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors

Robertson, Mark J., Horatscheck, André, Sauer, Samantha, von Kleist, Lisa, Baker, Jennifer R. , Stahlschmidt, Wiebke, Nazaré, Marc, Whiting, Ainslie, Chau, Ngoc, Robinson, Phillip J., Haucke, Volker, and McCluskey, Adam (2016) 5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors. Organic and Biomolecular Chemistry, 14 (47). pp. 11266-11278.

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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.

Item ID: 47803
Item Type: Article (Research - C1)
ISSN: 1477-0539
Funders: Deutsche Forschungsgemeinschaft (DFG), Australian Research Council (ARC), National Health and Medical Research Council (NHMRC), Ramaciotti Foundation (RF), Australian Cancer Research Foundation, Cancer Institute NSW (CI)
Projects and Grants: DFG #SFB765/B04 & SFB958, NHMRC #GNT1069493, GNT1047070 & GNT1022218
Date Deposited: 15 Mar 2017 01:43
FoR Codes: 03 CHEMICAL SCIENCES > 0305 Organic Chemistry > 030503 Organic Chemical Synthesis @ 50%
03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030401 Biologically Active Molecules @ 50%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 100%
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