Computational Study of Mutagen X

Mutagen X (MX), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is one of the most potent directing acting mutagen ever tested in SAL TA100 assay. Although MX analogues have been synthesized, tested for mutagenicity and modeled by structure-activity relationship (SAR) methods, the mechanism of interaction of these compounds with DNA to produce their remarkable mutagenic potency remains unresolved. MX exists as an equilibrium mixture of both ring and open form in water. This equilibrium is very fast for Ames test. Because the mixture is not separable by experimental methods, it is not clear which one is really responsible for the observed mutagenicity. There have been many debates that which one is really responsible for the observed mutagenicity. We used ab initio methods for the MX analogues. It seems both ring and open form could react with DNA bases as electrophiles. However, every open form has consistently lower LUMO energy than corresponding ring form. It is reasonable to assume that the major reaction will go through via open form for MX analogues. This suggest that the open form is more likely really mutagenic.