Structure-activity relationship studies of acridones as potential antipsoriatic agents. 1. Synthesis and antiproliferative activity of simple N-unsubstituted 10H-acridin-9-ones against human keratinocyte growth.
A series of N-unsubstituted hydroxy-10H-acridin-9-ones were synthesized and evaluated for inhibitory action against HaCaT keratinocyte growth, in order to explore their potential as antipsoriatic agents. For structure-activity relationship studies, the number and position of the hydroxyl groups were modified, the oxygen functions substituted or replaced, or additional functional groups were introduced into the acridone scaffold. 1,8-Dihydroxy-10H-acridin-9-one (4), which is an aza-analogue of the antipsoriatic anthralin, was only marginally active. However, 1,3-dihydroxy-substituted 5ee was the most potent acridone within this series and inhibited keratinocyte growth with an IC(50) value comparable to that of anthralin. In contrast to anthralin, nearly all members of the acridone series were devoid of radical generating properties, which were determined by their capability to interact with the free radical 2,2-diphenyl-1-picrylhydrazyl. Structures with a phenolic hydroxyl or an aromatic amine arranged ortho or para to the acridone NH group were exceptions. Also in contrast to anthralin, membrane-damaging effects as documented by the release of lactate dehydrogenase into the culture medium were not observed for acridones.
Putic
Aleksandar
A
Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University of Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Stecher
Lambert
L
Prinz
Helge
H
Müller
Klaus
K
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D054831:Acridones; D001713:Biphenyl Compounds / Q000737:chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects*; D009584:Nitrogen / Q000737:chemistry*; D010851:Picrates / Q000737:chemistry; D011565:Psoriasis / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D000166:Acridines; D054831:Acridones; D001713:Biphenyl Compounds; D010851:Picrates; C041300:acridone; C004931:1,1-diphenyl-2-picrylhydrazyl; D009584:Nitrogen