2-arylalkyl-substituted anthracenones as inhibitors of 12-lipoxygenase enzymes. 1. Structure-activity relationships of the terminal aryl ring.
A series of 2-arylmethyl-substituted anthracenones were synthesized and tested as inhibitors of three types of 12-lipoxygenase isoforms in epidermal homogenate of mice, bovine platelets and porcine leucocytes. Their inhibitory activities were compared with those to inhibit the 5-lipoxygenase enzyme in bovine leucocytes. Structure-activity relationships are described with particular emphasis on modifications of the terminal aryl nucleus. The ability of the compounds to selectively inhibit the 12-lipoxygenase enzymes was dependent on a high overall lipophilicity of the inhibitor, whereas compounds with decreased lipophilicity were also inhibitors of the 5-LO enzyme. Among the more lipophilic inhibitors, the unsubstituted 2-phenylmethyl analogue 6a as well as the carboxylic acid ester 6q appeared to be selective inhibitors of platelet-type 12-LO isoform.
Müller
K
K
Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische Chemie, Hittorfstrasse 58-62, D-48149, Münster, Germany. kmuller@uni-muenster.de
Altmann
R
R
Prinz
H
H
D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology; D002417:Cattle; D004353:Drug Evaluation, Preclinical; D004817:Epidermis / Q000201:enzymology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007962:Leukocytes / Q000201:enzymology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D013329:Structure-Activity Relationship; D013552:Swine
D000873:Anthracenes; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D001092:Arachidonate 12-Lipoxygenase