Structure-activity relationship in halogen and alkyl substituted allyl and allylic compounds: Correlation of alkylating and mutagenic properties

Abstract

In a series of allylic chloroolefins and their non-allylic isomers the significance of the allylic structure and the influence of methyl and chlorine substituents on the direct mutagenic activity in Salmonella typhimurium (TA 100) was tested. The direct mutagenic potentials correlate well with the alkylating activities as measured in the nitrobenzyl-pyridine (NBP) test. In contrast to allyl chloride, the vinylic chloroolefins 2-chloro-1-propene and 1-chloro-1-propene did not show any direct mutagenic and alkylating properties. Monomethylated allylic chlorides are six to thirty times more mutagenic: 3-chloro-2-methyl-1-propene <3-chloro-1-butene <1-chloro-2-butene. The non-allylic isomers 2-chloro-2-butene and 4-chloro-1-butene, however, are not directly mutagenic. In spite of a higher alkylating potency, bimethylated allylic chlorides did not show an increase in mutagenicity if compared with monomethylated derivatives: 3-chloro-2-methyl-1-butene <1-chloro-2-methyl-2-butene. 1-Chloro-1-cyclohexene lacks mutagenic and alkylating activity, whereas 3-chloro-1-cyclohexene is comparable to allyl chloride in both respects. Dichloropropenes are also more directly mutagenic than allyl chloride: 2,3-dichloro-1-propene ⪡ trans-< cis-1,3-dichloropropene. Benzyl chloride exerted the highest alkylating activity of all substances tested in this survey, and is about fifty times more mutagenic than allyl chloride. Addition of rat liver S-9 mix was followed by a distinct decrease in the mutagehicity of directly mutagenic substances, the only exception being 2,3-dichloro-1-propene, which demonstrated an increase by a factor of 35. Under the same conditions, vinylic chloroolefins are activated and become mutagenic to various degrees. Only 1-chloro-1-cyclohexene and the homoallylic compound 4-chloro-1-butene are negative both in the presence and absence of S-9 mix.