BROMINE-SUBSTITUTED, CHLORINE-SUBSTITUTED, AND MIXED HALOGEN-SUBSTITUTED 4-METHYL-2(5H)-FURANONES - SYNTHESIS AND MUTAGENIC EFFECTS OF HALOGEN AND HYDROXYL GROUP REPLACEMENTS

The versatility of 4-(hydroxymethyl)-2(5H)-furanone as a starting poin t for the synthesis of several bromine and mixed halogen analogues of the potent water mutagen 3-chloro-4( dichloromethyl)-5-hydroxy-2(5H)-f uranone (MX) has been demonstrated. However, in some preparations the yields of desired products were lower for bromine-than chlorine-substi tuted counterparts. A total of 12 bromine-, chlorine-, and mixed halog en-substituted 4-methyl-2(5H)-furanones were tested repeatedly in 10 i ndependent experiments for levels of Salmonella typhimurium (TA100) mu tagenicities. The purpose of these experiments was to determine the mu tagenic response to changing halogen content, type, and position as we ll as to learn the measure of these responses in the presence and abse nce of the C-5 OH group. Mutagenicities reached levels of 10(3) and 10 (2) rev/nmol for all trihalo- and dihalo-4-methyl-5-hydroxy-2(5H)-fura nones, respectively, notwithstanding substitutions by bromine or chlor ine. Trihalides lacking the C-5 hydroxyl group possessed mutagenicitie s of the order of 10(2) rev/nmol, while hydroxyl group absence in the dihalides resulted in potency levels of slightly less than 10 rev/ nmo l. Pairwise comparisons of compound mutagenicities showed that overall the C-5 H-by-OH replacement and, next in importance, increasing the n umber of C-6 halogens from one to two resulted in the greatest enhance ments of mutagenicities. However, in comparing compound pairs within t wo different sets of four di-and trihalides, it was observed that repl acement of a C-5 H by OH enhanced mutagenicity more for the dihalides than the trihalides, indicating that increasing the C-6 halogen number simultaneously with replacing C-5 H by OH results in a nonlinear, add itive enhancement. For fewer than half of the compound pairs compared, changing the C-6 halogen from chlorine to bromine resulted in small i ncreases in mutagenicity, and for the remaining compound pairs, no inc rease could be discerned. This result points to the relative unimporta nce of only C-6 halogen type as a determinant of mutagenicity. Similar ly, no impact on mutagenicity was observed for changing only the halog en type attached to C-3.