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Iminochromene Inhibitors of Dynamins I and II GTPase Activity and Endocytosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 10, 4094-4102 p.Article in journal (Refereed) Published
Abstract [en]

Herein we report the synthesis of discrete iminochromene (“iminodyn”) libraries (1438) 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.

Place, publisher, year, edition, pages
2010. Vol. 53, no 10, 4094-4102 p.
National Category
Pharmaceutical Sciences
Research subject
Organic Pharmaceutical Chemistry
URN: urn:nbn:se:uu:diva-142262DOI: 10.1021/jm100119cPubMedID: 20426422OAI: oai:DiVA.org:uu-142262DiVA: diva2:387225
Available from: 2011-01-13 Created: 2011-01-13 Last updated: 2013-10-22Bibliographically approved

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