Structure-activity relationships for epidermal ornithine decarboxylase induction and skin tumor promotion by anthrones.
The present study was designed to compare the skin tumor promoting and epidermal ornithine decarboxylase (ODC) inducing activities of various structural analogs of anthralin (1,8-dihydroxy-9-anthrone) and chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone). Groups of 30 SENCAR mice each were initiated with 7,12-dimethylbenz[a]anthracene and 2 weeks later promoted with once- or twice-weekly applications of various doses of these anthrone derivatives. Carbon-10 (C10)-acyl derivatives of anthralin were active skin tumor promoters in the range of 25-440 nmol per mouse. 10-Acetylanthralin was significantly more active than 10-myristoyl-anthralin at low doses (e.g. 25 and 50 nmol per mouse) and nearly as potent as the unsubstituted compound. Higher doses (greater than or equal to 100 nmol per mouse) of this derivative were toxic, hence, reducing the final papilloma response. On a relative activity scale where anthralin is 1.0, these derivatives had activities that were approximately 0.7 and 0.2, respectively. 10,10-Dipropylanthralin was totally inactive at the doses tested. C6-Substituted derivatives of chrysarobin demonstrated diverse tumor promoting activities when tested in the range of 25-440 nmol per mouse. On a relative activity scale where chrysarobin is 1.0, 6-methoxychrysarobin (physcion anthrone) was approximately 0.9, whereas 6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanic acid (1,8-dihydroxy-3-methyl-9,10-anthraquinone) was also inactive as a tumor promoter at the doses tested. In general, the tumor promoting activities of these anthrone derivatives correlated very well with their ability to induce epidermal ODC after a single topical application indicating an important role for this enzyme in skin tumor promotion by anthones. The ability of C10-substituted derivatives of anthralin to undergo base catalyzed oxidation in vitro correlated with both ODC inducing and tumor promoting activities. In addition, copper(II)bis(diisopropylsalicylate) was found to inhibit both ODC induction and skin tumor promotion by chrysarobin. These latter data, when taken together, suggest a role for oxidation at C10 in skin tumor promotion by anthrone derivatives.
DiGiovanni
J
J
University of Texas System Cancer Center, Smithville 78957.
Kruszewski
F H
FH
Coombs
M M
MM
Bhatt
T S
TS
Pezeshk
A
A
D000818:Animals; D000873:Anthracenes / Q000378:metabolism / Q000633:toxicity*; D000875:Anthralin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005609:Free Radicals; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D012459:Salicylates / Q000494:pharmacology; D012867:Skin / Q000201:enzymology*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013329:Structure-Activity Relationship
D000873:Anthracenes; D005609:Free Radicals; D012459:Salicylates; C030865:copper bis(3,5-diisopropylsalicylate); C013883:chrysarobin; D009955:Ornithine Decarboxylase; D000875:Anthralin