2-Arylalkyl-substituted anthracenones as inhibitors of 12-lipoxygenase enzymes. 2. Structure-activity relationships of the linker chain.
A series of 2-arylalkyl-substituted anthracenones were tested as inhibitors of three types of 12-lipoxygenase isoforms in epidermal homogenate of mice, bovine platelets and porcine leukocytes. Their inhibitory activities were compared with those to inhibit the 5-lipoxygenase enzyme in bovine leukocytes. The compounds were synthesised by Marschalk, Wittig or Horner-Emmons reaction at the anthracenedione stage and then reduced to the anthracenones. Structure-activity relationship for the chain linking the anthracenone nucleus and the phenyl ring terminus was investigated. The 2-phenylethyl analogues were among the most potent inhibitors, and 3,4-dimethoxy-substituted 10f was identified as a selective inhibitor of the 12-LO enzymes over 5-LO. Selectivity for 12-LO isoforms was observed with an increase in the overall lipophilicity of the inhibitors. However, none of the linker chains of the 2-substituted anthracenones provided inhibitors that were able to discriminate between the 12-LO isoforms.
Muller
Klaus
K
Westfalische Wilhelms-Universitat Munster, Institut fur Pharmazeutische und Medizinische Chemie, Hittorfstrasse 58-62, D-48149 Munster, Germany. kmuller@uni-muenster.de
Altmann
Reinhold
R
Prinz
Helge
H
D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology; D002417:Cattle; D066298:In Vitro Techniques; D007962:Leukocytes / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D051379:Mice; D012867:Skin / Q000201:enzymology; D013329:Structure-Activity Relationship; D013552:Swine
D000873:Anthracenes; D016859:Lipoxygenase Inhibitors