Antipsoriatic anthrones with modulated redox properties. 5. Potent inhibition of human keratinocyte growth, induction of keratinocyte differentiation, and reduced membrane damage by novel 10-arylacetyl-1,8-dihydroxy-9(10H)-anthracenones

The synthesis and structure-activity relationships (SARs) of a series of no vel 10-arylacetyl-1,8-dihydroxy-9(10H)-anthracenones are described. Acylati on of anthralin with either the appropriate arylacetyl chlorides or arylace tic acids in the presence of pyridine or via the coupling agent dicyclohexy lcarbodiimide (DCC), respectively, furnished this structural class of antip soriatic agents. Potential antipsoriatic activity was evaluated in compleme ntary assays specifically addressed to three important aspects of psoriasis . First, several compounds were identified which are equally potent as inhi bitors of human keratinocyte growth as the antipsoriatic agent anthralin. F urthermore, improved ratio of antiproliferative activity to cytotoxicity is demonstrated by the reduced potential of the novel analogues to induce mem brane damage, which is a benefit of their reduced ability to generate oxyge n radicals as documented by deoxyribose degradation. Second, analogue 3o be aring a hydroxamate functional group was also a highly potent inhibitor of LTB4 biosynthesis in addition to its excellent antiproliferative activity. SARs of these inhibitors of both keratinocyte growth and LTB4 biosynthesis with respect to the nature of the para-substitution in the 10-phenylacetyl side chain are discussed. Third, the compounds were also evaluated for thei r ability to induce the formation of cornified envelope protein in keratino cytes. Cross-linking of cellular protein as a marker of terminal differenti ation of keratinocytes was observed for many 10-arylacetyl analogues at con centrations required to arrest cell growth. This newly uncovered activity o f the novel anthracenones suggests antipsoriatic potential with respect to disturbance of keratinocyte differentiation, in addition to hyperproliferat ive and inflammatory aspects of psoriasis.