Development of 1,8-Naphthalimides as Clathrin Inhibitors

摘要

We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition~1). Initial screening of a ～17 000 small molecule ChemBioNet library identified 1. Screening of an existing inhouse 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, IC_(50) ≈ 18 μM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC_(50) values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC_(50) 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 IC_(50) ≈ 6.9 μM, is the most potent clathrin terminal domain?amphiphysin inhibitor reported to date.