SIMPLE ANALOGS OF ANTHRALIN - UNUSUAL SPECIFICITY OF STRUCTURE AND ANTIPROLIFERATIVE ACTIVITY

Fifty-nine simple analogues of the antipsoriatic agent, anthralin, hav e been prepared by modifying the positions of the 1,8-hydroxyl groups, replacement of the hydroxyl groups, substitution at the oxygen functi ons, introduction of additional functional groups into various positio ns of the anthracenone nucleus, or removal of particular structural el ements. The compounds were evaluated for their antiproliferative actio n against human keratinocytes and inhibition of the generation of leuk otriene B-4 in polymorphonuclear leukocytes, which may be useful to re solve the proliferative and inflammatory aspects of psoriasis, respect ively. Even though many anthracenones were more potent inhibitors of l eukotriene biosynthesis than anthralin, none of the compounds was subs tantially more effective as this drug in suppressing keratinocyte cell growth. There is an absolute requirement for two hydroxyl groups peri to a hydrogen bond acceptor such as a keto or an imino group for high potency. Ln addition to further delineating the nature of the pharmac ophore for this class of compounds, also naphthalenedione with a peri hydroxyl group was identified as a pharmacophore with antiproliferativ e activity against keratinocyte growth.