Fluorinated phenylcyclopropylamines. 2. Effects of aromatic ring substitution and of absolute configuration on inhibition of microbial tyramine oxidase.
A series of para-substituted diastereopure cis- and trans-2-fluoro-2-arylcyclopropylamines were synthesized and these were investigated as inhibitors of microbial tyramine oxidase from Arthrobacter sp. All compounds were shown to be competitive inhibitors of this enzyme. The nature of the para-substituents in the more potent trans-isomer (cis-relationship between fluorine and the amino group) of 2-fluoro-2-arylcyclopropylamine influenced the inhibitory potency in a consistent fashion. Thus, electron-withdrawing groups (F, Cl) slightly decreased the activity, while the methyl group (+ I substituent) increased the activity by a factor of ca. 7 compared to trans-2-fluoro-2-phenylcyclopropylamine and by a factor of 90 compared to tranylcypromine. Activity also was strongly dependent on the absolute configuration. The (1S,2S)-enantiomer of 2-fluoro-2-phenylcyclopropylamine was an excellent inhibitor of tyramine oxidase whereas the (1R,2R)-enantiomer was essentially devoid of activity.
Rosen
Thomas C
TC
Organisch-Chemisches Institut, Universität Münster, Corrensstr. 40, D-48149 Münster, Germany.
Yoshida
Shinichi
S
Fröhlich
Roland
R
Kirk
Kenneth L
KL
Haufe
Günter
G
D001173:Arthrobacter / Q000201:enzymology*; D018360:Crystallography, X-Ray; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000737:chemistry; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011437:Propylamines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
C484867:2-fluoro-2-phenylcyclopropylamine; D008996:Monoamine Oxidase Inhibitors; D011437:Propylamines; D014191:Tranylcypromine; D008995:Monoamine Oxidase