Synthesis and Mutagenicity of Modified Chrysenes Related to the Carcinogen, 5-Methylchrysene

Stephen S. Hecht, Myrna Loy, Robert Mazzarese, Dietrich Hoffmann

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30 Scopus citations

Abstract

The environmental carcinogen, 5-methylchrysene (1), is more carcinogenic on mouse skin and more mutagenic toward Salmonella typhimurium than any of the other methylchrysene isomers or chrysene and has activity comparable to benzo[α]pyrene. To investigate the modes of metabolic activation of 1, a series of modified chrysene derivatives was synthesized. The following compounds were prepared: l-fluoro-5-methylchrysene (l-F-5-MeC, 2), 3-F-5-MeC (3), 6-F-5-MeC (4), 7-F-5-MeC (5), 9-F-5-MeC (6), ll-F-5-MeC (7), 12-F-5-MeC (8), l-fluoro-4-methylchrysene (9), 6-methoxy-5-methylchrysene (10), 12-methoxy-5-methylchrysene (11) and 5-methoxychrysene (12). Compounds 2, 3 and 5-12 were prepared by photocyclization of the appropriate alkene precursors, which, in turn, were prepared by either Grignard reactions and dehydration (5-8, 11), Wittig reactions (2, 3, 9), or enol ether formation (10, 12). 6-F-5-MeC (4) was prepared by reaction of 5,6-dihydro-5,6-dihydroxy-5-methylchrysene with diethylaminosulfur trifluoride. All compounds were assayed for mutagenicity toward S. typhimurium strain TA-100. Fluoro derivatives 2, 3 and 8 were less mutagenic than 1, whereas 4, 6 and 7 were as mutagenic; 5 was toxic to the bacteria. Methoxy compounds 10-12 were less mutagenic than 1, as was 5,12-dimethylchrysene; 9 was more mutagenic than 4-methylchrysene. These results indicated that the 12, 1 and 3 positions of 1 were involved in metabolic activation and the 6, 9 and 11 positions were not; the nonplanarity of 1 apparently contributes to its mutagenic activity. A 1,2-dihydrodiol 3,4-epoxide may be the ultimate mutagen derived from 1 and the adjacent 12-peri position may be involved in its formation.

Original languageEnglish (US)
Pages (from-to)38-44
Number of pages7
JournalJournal of Medicinal Chemistry
Volume21
Issue number1
DOIs
StatePublished - Jan 1 1978

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