Show simple item record

dc.contributor.authorUcal, S
dc.contributor.authorHäkkinen, MR
dc.contributor.authorAlanne, AL
dc.contributor.authorAlhonen, L
dc.contributor.authorVepsäläinen, J
dc.contributor.authorKeinänen, TA
dc.contributor.authorHyvönen, MT
dc.date.accessioned2018-05-17T10:42:33Z
dc.date.available2018-05-17T10:42:33Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6618
dc.description.abstractReplacing protium with deuterium is an efficient method to modulate drug metabolism. N-alkylated polyamine analogues are polyamine antimetabolites with proven anticancer efficacy. We have characterized earlier the preferred metabolic routes of N1,N12-diethylspermine (DESpm), N1-benzyl-N12-ethylspermine (BnEtSpm) and N1,N12-dibenzylspermine (DBSpm) by human recombinant spermine oxidase (SMOX) and acetylpolyamine oxidase (APAO). Here, we studied the above analogues, their variably deuterated counterparts and their metabolites as substrates and inhibitors of APAO, SMOX, semicarbazide-sensitive amine oxidase (SSAO), diamine oxidase (DAO) and monoamine oxidases. We found that targeted deuteration efficiently redirected the preferable cleavage site and suppressed reaction rate by APAO and SMOX in vitro. We found a three- to six-fold decline in Vmax with moderate variable effect on Km when deuterium was located at the preferred hydrogen abstraction site of the analogue. We also found some of the metabolites to be potent inhibitors of DAO and SSAO. Surprisingly, analogue deuteration did not markedly alter the anti-proliferative efficacy of the drugs in DU145 prostate cancer cells, while in mouse embryonic fibroblasts, which had higher basal APAO and SMOX activities, moderate effect was observed. Interestingly, the anti-proliferative efficacy of the analogues did not correlate with their ability to suppress polyamine biosynthetic enzymes, induce spermidine/spermine-N1-acetyltransferase or deplete intracellular polyamine levels, but correlated with their ability to induce SMOX. Our data show that selective deuteration of N-alkyl polyamine analogues enables metabolic switching, offering the means for selective generation of bioactive metabolites inhibiting, e.g. SSAO and DAO, thus setting a novel basis for in vivo studies of this class of analogues.
dc.language.isoenglanti
dc.publisherPortland Press Ltd.
dc.relation.ispartofseriesBIOCHEMICAL JOURNAL
dc.relation.urihttp://dx.doi.org/10.1042/BCJ20170887
dc.rightsAll rights reserved
dc.subjectkinetic isotope effect
dc.subjectmetabolic switching
dc.subjectdeuterium
dc.subjectflavin-dependent amine oxidoreductases
dc.subjectspermine oxidase
dc.subjectacetylpolyamine oxidase
dc.subjectMDL 72527
dc.subjectpolyamines
dc.subjectpolyamine analogues
dc.titleControlling of N-Alkylpolyamine Analogue Metabolism by Selective Deuteration
dc.description.versionfinal draft
dc.contributor.departmentSchool of Pharmacy, Activities
uef.solecris.id51831915en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© Authors
dc.relation.doi10.1042/BCJ20170887
dc.description.reviewstatuspeerReviewed
dc.format.pagerange663-676
dc.relation.issn0264-6021
dc.relation.issue3
dc.relation.volume475
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessEi


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record