Structure-activity relationships of bacterial mutagens related to 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone: an emphasis on the effect of stepwise removal of chlorine from the dichloromethyl group.
The Salmonella typhimurium (TA100) mutagenicities of six structural analogues of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) were determined and compared. These were also compared to previously determined mutagenicities for another four analogues. This study was conducted for the primary purpose of ascertaining the effect of C-6 chlorine-by-hydrogen replacement on mutagenicity. The compounds assayed were 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (3), 3-chloro-4-(chloromethyl)-2(5H)-furanone (4), 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (7), 3-chloro-4-methyl-2(5H)-furanone (8), 4-methyl-5-hydroxy-2(5H)-furanone (9), and 4-methyl-2(5H)-furanone (10). Compounds 3, 4, and 7 were mutagenic whereas 8-10 were not. All six compounds were stable under assay conditions. Mutagenicity data for the three active compounds were combined with data of another four active compounds studied previously to obtain an expanded data set. Mutagenicities of the seven compounds were compared, pairwise, in 21 comparisons and then by multiple regression analysis. On the average, chlorine-by-hydrogen replacement of a single chlorine located at a chloromethyl group (C-6) had a markedly greater effect in reducing mutagenicity than a similar replacement at C-3 or a hydroxyl-by-hydrogen replacement at C-5. The chlorine-by-hydrogen replacement at C-6 of compound 3 resulted in the greatest mutagenicity reduction of any single replacement and amounted to a 10(3)-fold diminished mutagenicity.
LaLonde
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Department of Chemistry, College of Environmental Science and Forestry, State University of New York, Syracuse 13210.
Cook
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Perakyla
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D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000235:genetics*; D002713:Chlorine / Q000737:chemistry; D002849:Chromatography, Gas; D005663:Furans / Q000737:chemistry / Q000633:toxicity*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D012044:Regression Analysis; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D005663:Furans; D009153:Mutagens; D002713:Chlorine; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone