Cis-Cyclopropylamines as Mechanism-Based Inhibitors of Monoamine Oxidases

dc.contributor.author Malcomson, Thomas
dc.contributor.author Yelekçi, Kemal
dc.contributor.author Yelekçi, Kemal
dc.contributor.author Borrello, Maria Teresa
dc.contributor.author Ganesan, A.
dc.contributor.author Semina, Elena
dc.contributor.author De Kimpe, Norbert
dc.contributor.author Mangelinckx, Sven
dc.contributor.author Ramsay, Rona R.
dc.contributor.other Molecular Biology and Genetics
dc.date.accessioned 2019-06-27T08:02:14Z
dc.date.available 2019-06-27T08:02:14Z
dc.date.issued 2015
dc.department Fakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümü en_US
dc.description.abstract Cyclopropylamines inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1) provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition most compounds gave high IC50 values with MAO A but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme the inhibition was irreversible for both MAOA and MAOB and the activity was not restored by dilution. Spectral changes during inactivation of MAOA included bleaching at 456nm and an increased absorbance at 400nm consistent with flavin modification. These derivatives are MAOB-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine with an IC50 of 5nm for MAOB and 170nm for MAOA after 30min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine so may be studied as a lead for selective inhibitors of MAOB that do not inhibit LSD1. en_US]
dc.identifier.citationcount 30
dc.identifier.doi 10.1111/febs.13260 en_US
dc.identifier.endpage 3198
dc.identifier.issn 1742-464X en_US
dc.identifier.issn 1742-4658 en_US
dc.identifier.issn 1742-464X
dc.identifier.issn 1742-4658
dc.identifier.issue 16
dc.identifier.pmid 25755053 en_US
dc.identifier.scopus 2-s2.0-84939250541 en_US
dc.identifier.scopusquality Q1
dc.identifier.startpage 3190 en_US
dc.identifier.uri https://hdl.handle.net/20.500.12469/578
dc.identifier.uri https://doi.org/10.1111/febs.13260
dc.identifier.volume 282 en_US
dc.identifier.wos WOS:000360016700015 en_US
dc.identifier.wosquality Q1
dc.institutionauthor Yelekçi, Kemal en_US
dc.language.iso en en_US
dc.publisher Wiley-Blackwell en_US
dc.relation.journal Febs Journal en_US
dc.relation.publicationcategory Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı en_US
dc.rights info:eu-repo/semantics/openAccess en_US
dc.scopus.citedbyCount 33
dc.subject Cyclopropylamine en_US
dc.subject Docking en_US
dc.subject Flavin adduct en_US
dc.subject Mechanism-based inhibitor en_US
dc.subject Monoamine oxidase en_US
dc.title Cis-Cyclopropylamines as Mechanism-Based Inhibitors of Monoamine Oxidases en_US
dc.type Article en_US
dc.wos.citedbyCount 33
dspace.entity.type Publication
relation.isAuthorOfPublication 9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery 9407938e-3d31-453b-9199-aaa8280a66c5
relation.isOrgUnitOfPublication 71ce8622-7449-4a6a-8fad-44d881416546
relation.isOrgUnitOfPublication.latestForDiscovery 71ce8622-7449-4a6a-8fad-44d881416546

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