Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/62357
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dc.contributor.authorHill, T.en
dc.contributor.authorMariana, A.en
dc.contributor.authorGordon, C.en
dc.contributor.authorOdell, L.en
dc.contributor.authorRobertson, M.en
dc.contributor.authorMcGeachie, A.en
dc.contributor.authorChau, N.en
dc.contributor.authorDaniel, J.en
dc.contributor.authorGorgani, N.en
dc.contributor.authorRobinson, P.en
dc.contributor.authorMcCluskey, A.en
dc.date.issued2010en
dc.identifier.citationJournal of Medicinal Chemistry, 2010; 53(10):4094-4102en
dc.identifier.issn0022-2623en
dc.identifier.issn1520-4804en
dc.identifier.urihttp://hdl.handle.net/2440/62357-
dc.description.abstractHerein 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.en
dc.description.statementofresponsibilityTimothy A. Hill, Anna Mariana, Christopher P. Gordon, Luke R. Odell, Mark J. Robertson, Andrew B. McGeachie, Ngoc Chau, James A. Daniel, Nick N. Gorgani, Phillip J. Robinson, and Adam McCluskeyen
dc.language.isoenen
dc.publisherAmer Chemical Socen
dc.rightsCopyright © 2010 American Chemical Societyen
dc.subjectSynaptic Vesicles; Cell Line, Tumor; Synaptosomes; Animals; Sheep; Humans; Rats; Rats, Sprague-Dawley; Benzopyrans; Dynamin I; Dynamin II; Receptors, Transferrin; Endocytosis; Structure-Activity Relationship; Kinetics; Male; In Vitro Techniquesen
dc.titleIminochromene inhibitors of dynamins I and II GTPase activity and endocytosisen
dc.typeJournal articleen
dc.identifier.doi10.1021/jm100119cen
pubs.publication-statusPublisheden
Appears in Collections:Paediatrics publications

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