Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/932394
- Title
- Iminochromene inhibitors of Dynamins I and II GTPase activity and Endocytosis
- Author/Creator
-
Hill, Timothy A.;
Mariana, Anna;
McCluskey, Adam;
Gordon, Christopher P.;
Odell, Luke R.;
Robertson, Mark J.;
McGeachie, Andrew B.;
Chau, Ngoc;
Daniel, James A.;
Gorgani, Nick N.;
Robinson, Phillip J.
- Institution
- The University of Newcastle. Faculty of Science & Information Technology, School of Environmental and Life Sciences
- Description
- Herein we report the synthesis of discrete iminochromene (“iminodyn”) libraries (14−38) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC₅₀ values of 260 nM to 100 μM), 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) (IC₅₀ 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 IC₅₀ values of 10.7 ± 4.5 and 99.5 ± 1.7 μM, respectively. The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.
- Relation
- Journal of Medicinal Chemistry Vol. 53, Issue 10, p. 4094-4102
- Publisher Link
- http://dx.doi.org/10.1021/jm100119c
- Date
- 2010
- Publisher
- American Chemical Society
- Keyword(s)
-
receptor mediated endocytosis;
synaptic vesicle endocytosis;
coated pit;
formation
- Resource Type
- journal article
- Identifier
- http://hdl.handle.net/1959.13/932394
- Identifier
- ISSN:0022-2623
- Reviewed
15 Visitors
20 Hits
0 Downloads
