Simple analogues of anthralin: unusual specificity of structure and antiproliferative activity.
Fifty-nine simple analogues of the antipsoriatic agent, anthralin, have been prepared by modifying the positions of the 1,8-hydroxyl groups, replacement of the hydroxyl groups, substitution at the oxygen functions, introduction of additional functional groups into various positions of the anthracenone nucleus, or removal of particular structural elements. The compounds were evaluated for their antiproliferative action against human keratinocytes and inhibition of the generation of leukotriene B4 in polymorphonuclear leukocytes, which may be useful to resolve the proliferative and inflammatory aspects of psoriasis, respectively. Even though many anthracenones were more potent inhibitors of leukotriene biosynthesis than anthralin, none of the compounds was substantially 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. In addition to further delineating the nature of the pharmacophore for this class of compounds, also naphthalenedione with a peri hydroxyl group was identified as a pharmacophore with antiproliferative activity against keratinocyte growth.
Müller
K
K
Institut für Pharmazeutische Chemie, Westfälische Wilhelms-Universität Münster, Germany.
Prinz
H
H
Gawlik
I
I
Ziereis
K
K
Huang
H S
HS
D000287:Administration, Topical; D000818:Animals; D000875:Anthralin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D016877:Oxidants / Q000138:chemical synthesis / Q000494:pharmacology; D011565:Psoriasis / Q000188:drug therapy; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D016859:Lipoxygenase Inhibitors; D016877:Oxidants; D001094:Arachidonate 5-Lipoxygenase; D000875:Anthralin