Development of 1,8-naphthalimides as clathrin inhibitors

MacGregor, Kylie A., Robertson, Mark J., Young, Kelly A., von Kleist, Lisa, Stahlschmidt, Wiebke, Whiting, Ainslie, Chau, Ngoc , Robinson, Phillip J., Haucke, Volker, and McCluskey, Adam (2014) Development of 1,8-naphthalimides as clathrin inhibitors. Journal of Medicinal Chemistry, 57 (1). pp. 131-143.

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View at Publisher Website: http://dx.doi.org/10.1021/jm4015263
 
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Abstract

We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1). Initial screening of a ∼17 000 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as ∼80–120 µM clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, potassium salt (18, IC50 ≈ 18 µM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC50 values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 10 μM, respectively. Docking studies rationalized the structure–activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50 ≈ 6.9 µM, is the most potent clathrin terminal domain–amphiphysin inhibitor reported to date.

Item ID: 36831
Item Type: Article (Research - C1)
ISSN: 1520-4804
Funders: Deutsche Forschungsgemeinschaft (DFG), Australian Research Council (ARC), National Health and Medical Research Council (NHMRC), Ramaciotti Foundation, Australian Cancer Research Foundation, University of Newcastle
Projects and Grants: DFG (FG806-HA2686/3-2 and SFB765/ B04)
Date Deposited: 10 Dec 2014 07:31
FoR Codes: 03 CHEMICAL SCIENCES > 0305 Organic Chemistry > 030503 Organic Chemical Synthesis @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 100%
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