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Type: Journal article
Title: Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis
Author: Hill, T.
Mariana, A.
Gordon, C.
Odell, L.
Robertson, M.
McGeachie, A.
Chau, N.
Daniel, J.
Gorgani, N.
Robinson, P.
McCluskey, A.
Citation: Journal of Medicinal Chemistry, 2010; 53(10):4094-4102
Publisher: Amer Chemical Soc
Issue Date: 2010
ISSN: 0022-2623
Statement of
Timothy 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 McCluskey
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.
Keywords: Synaptic Vesicles
Cell Line, Tumor
Rats, Sprague-Dawley
Dynamin I
Dynamin II
Receptors, Transferrin
Structure-Activity Relationship
In Vitro Techniques
Rights: Copyright © 2010 American Chemical Society
DOI: 10.1021/jm100119c
Published version:
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