title: 1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity.
abstract: Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the Naphthaladyn™ series, with compounds 23 and 29 being the most active (IC50 of 19.1 ± 0.3 and 18.5 ± 1.7 μM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 μM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.
authors.affiliation: Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Abdel-Hamid
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Macgregor
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.forename: Anna
authors.initials: A
authors.lastname: Mariana
authors.forename: Ainslie
authors.initials: A
authors.lastname: Whiting
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D000588:Amines / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D002966:Clathrin / Q000378:metabolism; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000494:pharmacology; D017433:Protein Structure, Secondary
chemical_list: D000588:Amines; D002966:Clathrin; D004791:Enzyme Inhibitors; D053644:Naphthalimides; D010718:Phosphatidylserines; D006160:Guanosine Triphosphate; D034284:Dynamin I