Inhibition of in vitro prostaglandin and leukotriene biosyntheses by cinnamoyl-beta-phenethylamine and N-acyldopamine derivatives.
N-trans- and N-cis-Feruloyltyramines were isolated as the inhibitors of in vitro prostaglandin (PG) synthesis from an Indonesian medicinal plant, Ipomoea aquatica (Convolvulaceae). In order to clarify structure activity relationships, cinnamoyl-beta-phenethylamines with possible combinations of naturally occurring cinnamic acids and beta-phenethylamines were synthesized and tested for their inhibitory activities against PG synthetase and arachidonate 5-lipoxygenase. The compounds containing catechol groups such as N-caffeoyl-beta-phenethylamine (CaP) showed higher inhibitory effects on PG synthetase. The catechol group was found to be essential for the inhibition of arachidonate 5-lipoxygenase. The investigation of concentration dependent effects on PG biosynthesis revealed that CaP enhanced PG biosynthesis at a lower concentration range, whereas it inhibited the reaction at a higher concentration. The effects of CaP on each reaction step were investigated with purified PG endoperoxide synthase and microsomal PG synthetase. CaP inhibited the cyclooxygenase reaction, while it enhanced the hydroperoxidase reaction. N-Acyldopamines which contain catechol and lipophylic group were synthesized from dopamine and fatty acids to test their inhibitory effects on arachidonate 5-lipoxygenase. N-Linoleoyldopamine was the most active compound and its IC50 value was 2.3 nM in our assay system, in which an IC50 value of AA 861, a specific inhibitor of 5-lipoxygenase, was 8 nM.
Tseng
C F
CF
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Iwakami
S
S
Mikajiri
A
A
Shibuya
M
M
Hanaoka
F
F
Ebizuka
Y
Y
Padmawinata
K
K
Sankawa
U
U
D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004298:Dopamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry*; D013329:Structure-Activity Relationship
D002934:Cinnamates; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D010627:Phenethylamines; C075122:N-linoleoyldopamine; D004298:Dopamine