LaLonde R T, Bu L, Henwood A, Fiumano J, Zhang L
Department of Chemistry, College of Environmental Science and Forestry, State University of New York, Syracuse 13210-2786, USA.
Chem Res Toxicol. 1997 Dec;10(12):1427-36. doi: 10.1021/tx9701283.
The versatility of 4-(hydroxymethyl)-2(5H)-furanone as a starting point for the synthesis of several bromine and mixed halogen analogues of the potent water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) has been demonstrated. However, in some preparations the yields of desired products were lower for bromine- than chlorine-substituted counterparts. A total of 12 bromine-, chlorine-, and mixed halogen-substituted 4-methyl-2(5H)-furanones were tested repeatedly in 10 independent experiments for levels of Salmonella typhimurium (TA100) mutagenicities. The purpose of these experiments was to determine the mutagenic response to changing halogen content, type, and position as well as to learn the measure of these responses in the presence and absence 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)-furanones, respectively, notwithstanding substitutions by bromine or chlorine. Trihalides lacking the C-5 hydroxyl group possessed mutagenicities 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/ nmol. Pairwise comparisons of compound mutagenicities showed that overall the C-5 H-by-OH replacement and, next in importance, increasing the number of C-6 halogens from one to two resulted in the greatest enhancements of mutagenicities. However, in comparing compound pairs within two different sets of four di- and trihalides, it was observed that replacement 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, additive enhancement. For fewer than half of the compound pairs compared, changing the C-6 halogen from chlorine to bromine resulted in small increases in mutagenicity, and for the remaining compound pairs, no increase could be discerned. This result points to the relative unimportance of only C-6 halogen type as a determinant of mutagenicity. Similarly, no impact on mutagenicity was observed for changing only the halogen type attached to C-3.
已证明4-(羟甲基)-2(5H)-呋喃酮作为合成强效水致突变剂3-氯-4-(二氯甲基)-5-羟基-2(5H)-呋喃酮（MX）的几种溴代和混合卤代类似物的起始原料具有多功能性。然而，在某些制备过程中，所需产物的产率对于溴取代的类似物而言低于氯取代的类似物。总共12种溴代、氯代和混合卤代的4-甲基-2(5H)-呋喃酮在10个独立实验中针对鼠伤寒沙门氏菌（TA100）的诱变性水平进行了反复测试。这些实验的目的是确定对卤素含量、类型和位置变化的诱变反应，以及了解在有和没有C-5羟基的情况下这些反应的程度。所有三卤代和二卤代-4-甲基-5-羟基-2(5H)-呋喃酮的诱变性分别达到10(3)和10(2)回复突变/纳摩尔水平，尽管存在溴或氯取代。缺少C-5羟基的三卤化物的诱变性约为10(2)回复突变/纳摩尔，而二卤化物中缺少羟基导致效力水平略低于10回复突变/纳摩尔。化合物诱变性的成对比较表明，总体而言，用羟基取代C-5氢，其次重要的是将C-6卤素的数量从一个增加到两个，导致诱变性增强最大。然而，在比较两组不同的四种二卤化物和三卤化物中的化合物对时，观察到用羟基取代C-5氢对二卤化物的诱变性增强比对三卤化物更多，这表明在将C-5氢替换为羟基的同时增加C-6卤素数量会导致非线性的加性增强。在所比较的化合物对中，不到一半的情况下，将C-6卤素从氯变为溴会导致诱变性略有增加，而对于其余的化合物对，则没有观察到增加。这一结果表明仅C-6卤素类型作为诱变性决定因素的相对不重要性。同样，仅改变连接在C-3上的卤素类型对诱变性没有影响。
