Anthracene-9,10-diones as potential anticancer agents: bacterial mutation studies of amido-substituted derivatives reveal an unexpected lack of mutagenicity.
Fifteen anthracene-9,10-dione ("anthraquinone") derivatives with (omega-aminoalkyl)carboxamido substituents at the 1-, 2-, 1,4-, or 2, 6-ring positions were tested for bacterial mutagenicity in reverse-mutation assays using Salmonella typhimurium frameshift strains TA1538, TA98, and TA97a, in the presence and absence of a metabolic activation system prepared from the livers of rats treated with Aroclor 1254. Six of the compounds were also tested in S. typhimurium TA100 and Escherichia coli WP2uvrApKM101 strains, which carry mutations particularly sensitive to reversion by DNA base-pair substitution. Two structurally related compounds, mitoxantrone and bisantrene, were tested in parallel as positive controls. Mitoxantrone was mutagenic to S. typhimurium TA1538 and TA98, whereas bisantrene was weakly mutagenic to both these strains but strongly mutagenic toward the TA97a variant. By contrast, although they are also DNA-binding intercalators, none of the amide-functionalized anthracene-9,10-diones of the present study showed significant mutagenic activity in any of the bacterial strains examined. Further, neither substituent position nor systematic alterations in the nature of attached side chains appeared to induce mutagenicity with these agents, although other studies have shown that such structural factors markedly influence their cytotoxic potencies toward mammalian cells in vitro.
Venitt
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Section of Molecular Carcinogenesis and Cancer Research Campaign Biomolecular Structure Unit, The Institute of Cancer Research, Royal Cancer Hospital, Sutton, Surrey SM2 5NG, UK.
Crofton-Sleigh
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C
Agbandje
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Jenkins
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TC
Neidle
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D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008942:Mitoxantrone / Q000633:toxicity; D009153:Mutagens / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D009154:Mutation; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics
D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D009153:Mutagens; C031404:bisantrene; D008942:Mitoxantrone