ANTIPSORIATIC ANTHRONES WITH MODULATED REDOX PROPERTIES .2. NOVEL DERIVATIVES OF CHRYSAROBIN AND ISOCHRYSAROBIN - ANTIPROLIFERATIVE ACTIVITY AND 5-LIPOXYGENASE INHIBITION

A novel series of 2- and 3-substituted 1,8-dihydroxy-9(10H)-anthraceno nes were synthesized and tested for their inhibitory activity against 5-lipoxygenase (5-LO) in bovine polymorphonuclear leukocytes and the g rowth of human keratinocytes. Structure-activity relationships are dis cussed with respect to the following redox properties of the compounds : reactivity against 2,2-diphenyl-1-picrylhydrazyl, generation of hydr oxyl radicals as measured by deoxyribose degradation, and inhibition o f lipid peroxidation in model membranes. Inhibition of cell proliferat ion seemed to be related to these properties, whereas 5-LO inhibition was not. Within a class of structural analogs the activity against 5-L O, which was markedly improved as compared to that of the antipsoriati c drug anthralin, correlated well with tile overall lipophilicity. Eve n though a number of compounds in this series enhanced oxidative damag e to nonlipid molecules such as deoxyribose, their antioxidant propert ies predominate in membrane lipids. Among the prooxidant compounds wer e also the most potent antiproliferative agents (IC50 values in the 10 (-7) M range).