Development of 1,8-Naphthalimides as Clathrin Inhibitors

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 similar to 17 000 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as similar to 80-120 mu M clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, potassium salt (18, IC50 approximate to 18 mu M). A second library targeting the 4-aminobenzyl moiety was developed, and four anogues displayed comparable activity (26, 27, 28, 34 with IC50 values of 22, 16, 15, and 15 mu M respectively) with a further four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 10 mu M, 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 approximate to 6.9 mu M, is the most potent clathrin terminal domain-amphiphysin inhibitor reported to date.