Halogenated 2,5-pyrrolidinediones: synthesis, bacterial mutagenicity in Ames tester strain TA-100 and semi-empirical molecular orbital calculations.
The chloroimide 3,3-dichloro-4-(dichloromethylene)-2,5-pyrrolidinedione, a tetrachloroitaconimide, is the principal mutagen produced by chlorination of simulated poultry chiller water. It is the second most potent mutagenic disinfection by-product of chlorination ever reported. Six of seven new synthetic analogs of this compound are direct-acting mutagens in Ames tester strain TA-100. Computed energies of the lowest unoccupied molecular orbital (E(LUMO)) and of the radical anion stability (DeltaH(f)(rad)-DeltaH(f)) from MNDO-PM3 for the chloroimides show a quantitative correlation with the Ames TA-100 bacterial mutagenicity values. The molar mutagenicities of these direct acting mutagenic imides having an exocyclic double bond fit the same linear correlation (lnM(m) vs. E(LUMO); lnM(m) vs. DeltaH(f)(rad)--DeltaH(f)) as the chlorinated 2(5H)-furanones, including the potent mutagen MX, 3-chloro-4-(dichloro-methyl)-5-hydroxy-2(5H)-furanone, a by-product of water chlorination and paper bleaching with chlorine. Mutagenicity data for related haloimides having endocyclic double bonds are also given. For the same number of chlorine atoms, the imides with endocyclic double bonds have significantly higher Ames mutagenicity compared to their structural analogs with exocyclic double bonds, but do not follow the same E(LUMO) or DeltaH(f)(rad)-DeltaH(f) correlation as the exocyclic chloroimides and the chlorinated 2(5H)-furanones.
Freeman
B A
BA
US Department of Agriculture, Western Regional Research Center, Agricultural Research Service, 800 Buchanan Street, Albany, CA 94710, USA.
Wilson
R E
RE
Binder
R G
RG
Haddon
W F
WF
D000818:Animals; D003198:Computer Simulation; D004202:Disinfectants / Q000737:chemistry / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005511:Food Handling / Q000379:methods*; D005798:Genes, Bacterial / Q000187:drug effects; D008956:Models, Chemical; D015394:Molecular Structure; D009152:Mutagenicity Tests; D011200:Poultry; D011759:Pyrrolidines / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D018508:Water Purification / Q000379:methods*
D004202:Disinfectants; D011759:Pyrrolidines; D013388:Succinimides; D014874:Water Pollutants, Chemical; C426606:3,3-dichloro-4-(dichloromethylene)-2,5-pyrrolidinedione