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.