Certain 1,8-dihydroxy-9-anthrones have been used for the topical treatment of psoriasis. The therapeutic usefulness of these compounds is limited, however, by side effects including severe skin irritation and staining. Some anti-psoriatic anthrones are also tumor-promoters. The chemical mechanisms underlying the biological properties of 9-anthrones are uncertain, but are believed to be dependent upon the generation of free radical products such as 9-anthrone-10-yl radicals or secondary oxygen radicals such as O2.- or OH(.). The goal of this project is to gain a better understanding of the chemical and biochemical mechanisms of 1,8- dihydroxy-9-anthrone anti-psoriatic and tumor-promoting activities. Knowledge of these mechanisms will be useful for the design of more effective anti-psoriatic agents and will provide insights into fundamental mechanisms of cell growth and proliferation, which may also help in the understanding of other diseases such as cancer. The free radical species produced by a series of 9-anthrones of known tumor-promoting and anti- psoriatic activities have been investigated. Direct EPR and spin trapping techniques were utilized to detect radical products in aqueous buffers and in a keratinocyte culture system. Anthrone-10-yl radicals were identified as spin adducts of 2,6-dibromo- nitrosobenzene sulfonate (DBNBS). The ability to form these adducts was pH dependent and appears to be an important property of anti-psoriatic anthrones. A radical species was also detected by direct EPR in human keratinocytes after treatment with some biologically active anthrones. The formation of this species was shown to be light dependent. 5,5-Dimethyl-pyrroline-N-oxide (DMPO) was used to trap reactive oxygen radicals. Because all of the 9-anthrones tested generated significant amounts of DMPO spin adducts irrespective of their anti- psoriatic or tumor-promoting activities, we conclude that the ability to generate oxygen radicals is not sufficient to provide these activities, but may be involved in skin irritation.
