title: Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis.
abstract: Herein we report the synthesis of discrete iminochromene ("iminodyn") libraries (14-38) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC(50) values of 260 nM to 100 microM), with N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (23) (IC(50) values of 330 +/- 70, 450 +/- 50, and 260 +/- 80 nM, respectively) being the most potent. Five of the most potent iminodyns all inhibited dynamins I and II approximately equally. Iminodyn-22 displayed uncompetitive inhibition with respect to GTP. Selected iminodyns were evaluated for their ability to block receptor mediated endocytosis (RME, mediated by dynamin II) and synaptic vesicle endocytosis (SVE, mediated by dynamin I), with 17 showing no activity while 22 returned RME and SVE IC(50) values of 10.7 +/- 4.5 and 99.5 +/- 1.7 microM, respectively. The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.
authors.affiliation: Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hill
authors.forename: Anna
authors.initials: A
authors.lastname: Mariana
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gordon
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: Andrew B
authors.initials: AB
authors.lastname: McGeachie
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.forename: James A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Nick N
authors.initials: NN
authors.lastname: Gorgani
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D034284:Dynamin I / Q000037:antagonists & inhibitors*; D034285:Dynamin II / Q000037:antagonists & inhibitors*; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D011990:Receptors, Transferrin; D034284:Dynamin I; D034285:Dynamin II