Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis

Hill, Timothy A., Mariana, Anna, Gordon, Christopher P., Odell, Luke R., Robertson, Mark J., McGeachie, Andrew B., Chau, Ngoc, Daniel, James A., Gorgani, Nick N., Robinson, Phillip J., and McCluskey, Adam (2010) Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis. Journal of Medicinal Chemistry, 53 (10). pp. 4094-4102.

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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.

Item ID: 36827
Item Type: Article (Research - C1)
ISSN: 1520-4804
Funders: National Health and Medical Research Council (NHMRC), Children's Medical Research Institute (CMRI), University of Newcastle (UoN), Epilepsy Research Foundation
Date Deposited: 10 Dec 2014 07:31
FoR Codes: 03 CHEMICAL SCIENCES > 0305 Organic Chemistry > 030503 Organic Chemical Synthesis @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 100%
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