Effects of dialkoxylphenyl compounds with oxime group on macrophage function and the proliferation of lymphocytes.
Dialkoxyphenyl compounds have been reported to possess anti-inflammatory activity through inhibition of phosphodieseterase (PDE) type IV. In this study, a series of derivatives of dialkoxyphenyl compounds with an oxime group, which is generally known to be one of the biologically active functional groups, were prepared and evaluated for their ability to inhibit the production of inflammatory mediators in activated macrophages and the proliferation of lymphocytes. The structure-activity relationship (SAR) study with 12 compounds on tumour necrosis factor (TNF)-alpha inhibition, analysed by the oxime geometry and different size of spacers between the oxime and phenyl group, indicated that there might be at least three possible hydrogen bonding sites in the inhibitor binding pocket of PDE IV. Of them, compound 6 clearly displayed the highest inhibitory effect on in-vitro TNF-alpha production from lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Compound 6 also suppressed in-vivo TNF-alpha release from LPS-primed mice, a level comparable with that of the standard PDE IV inhibitor, rolipram. In addition, oxime compounds also significantly inhibited both nitric oxide production from activated RAW264.7 cells and T lymphocyte proliferation elicited by concanavalin A but not IL-2. The data suggest that the oxime group may act as a functional group, capable of interacting with the inhibitor-binding pocket of target PDE IV. Therefore, it is conceivable that compound 6 may have the potential either to be developed as a new anti-inflammatory drug or to be used to develop more potent analogues.
Yoo
Eun Sook
ES
Department of Pharmacology, College of Medicine, Cheju National University, Cheju, 690-756, South Korea.
Son
Ho Jung
HJ
Park
Joon Seok
JS
Kim
Ae Ra
AR
Baik
Kyong Up
KU
Park
Myung Hwan
MH
Cho
Jae Youl
JY
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D010091:Oximes; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4