Klein M, Voigtmann U, Haack T, Erdinger L, Boche G
Fachbereich Chemie, Phillips-Universität Marburg, Hans-Meerwein Strasse, 35032, Marburg, Germany.
Mutat Res. 2000 Apr 13;467(1):55-68. doi: 10.1016/s1383-5718(00)00012-7.
Eleven alkyl substituted derivatives of 4-nitrobiphenyl (4NBp) and two corresponding nitroso compounds were synthesised and tested for mutagenic potency in strains TA98 and TA100 of Salmonella typhimurium. The mutagenicity of compounds substituted ortho to the nitro group (3-methyl-, 3-ethyl-, 3-isopropyl-, 3-tertbutyl-, 3, 5-diethyl-, 3,5-diisopropyl-, and 3,5-ditertbutyl-4NBp) decreased with growing steric demand of the alkyl substituents in both tester strains. The most sterically hindered compounds were non-mutagenic even at highest concentrations. This reduction of mutagenicity is correlated with deviations from the coplanar orientation of the nitro group relative to the aromatic plane. Since a comparable decrease of mutagenicity for the nitroso compounds (4NOBp and 3-tertbutyl-4NOBp) was not observed, the first reduction step of non-planar nitro groups must be inhibited. Alkyl groups in the 2'-position of 4NBp (2'-methyl-, 2'-ethyl-, 2'-isopropyl-, and 2',4', 6'-trimethyl-4NBp) also reduced mutagenic activity with increasing size and removed it completely for the most sterically hindered species (2'-isopropyl-, 2',4',6'-trimethyl-4NBp). In this case, the co-planarity of the nitro group is not affected but the twisting of the two aromatic rings, which is associated with a less effective charge delocalisation of the nitrenium ion. The experimental mutagenicities of all nitro compounds were compared to predicted values, that are based on recently developed empirical equations. While there was reasonable correspondence for the parent compound (4NBp), its ortho methylated derivative (3-methyl-4NBp) and two highly hydrophobic dialkylated species (3,5-diisopropyl- and 3, 5-ditertbutyl-4NBp), predictions for all other alkyl substituted compounds were too high. Thus, steric parameters should be included to improve the general validity of predictions by means of quantitative structure-activity relationships (QSAR).
合成了11种4-硝基联苯（4NBp）的烷基取代衍生物和两种相应的亚硝基化合物，并在鼠伤寒沙门氏菌TA98和TA100菌株中测试了它们的诱变效力。在两个测试菌株中，硝基邻位取代的化合物（3-甲基-、3-乙基-、3-异丙基-、3-叔丁基-、3,5-二乙基-、3,5-二异丙基-和3,5-二叔丁基-4NBp）的诱变性随着烷基取代基空间需求的增加而降低。空间位阻最大的化合物即使在最高浓度下也无诱变作用。这种诱变性的降低与硝基相对于芳环平面的共面取向偏差有关。由于未观察到亚硝基化合物（4NOBp和3-叔丁基-4NOBp）的诱变性有类似降低，非平面硝基的第一步还原过程一定受到了抑制。4NBp 2'-位的烷基（2'-甲基-、2'-乙基-、2'-异丙基-和2',4',6'-三甲基-4NBp）也随着尺寸的增加而降低诱变活性，对于空间位阻最大的物种（2'-异丙基-、2',4',6'-三甲基-4NBp）则完全消除了诱变活性。在这种情况下，硝基的共面性未受影响，但两个芳环的扭曲与氮鎓离子电荷离域效率降低有关。将所有硝基化合物的实验诱变性与基于最近开发的经验方程预测的值进行了比较。虽然母体化合物（4NBp）、其邻位甲基化衍生物（3-甲基-4NBp）以及两种高度疏水的二烷基化物种（3,5-二异丙基-和3,5-二叔丁基-4NBp）的预测值与实际值有合理的对应关系，但所有其他烷基取代化合物的预测值都过高。因此，应纳入空间参数以通过定量构效关系（QSAR）提高预测结果的普遍有效性。
