Mutagenic properties of allylic and α,β-unsaturated compounds: Consideration of alkylating mechanisms

Abstract

1. Allyl and allylic compounds may exert alkylating activities by S_N¹, S_N² and S_N² mechanisms. This direct alkylating potential can be determined quantitatively by a modified 4-NBP (4-nitrobenzyl pyridine) test.

2. The alkylating activities in a systematically selected series of allyl and allylic compounds correlate well with the direct mutagenic potential as determined in the Ames test using Salmonella typhimurium TA 100 as tester strain.

3. The allylic structure is a prerequisite for these types of activities since structurally related molecules lacking the allylic moiety are inactive in this respect.

4. The potency of both the alkylating and mutagenic activity is determined by the strength of the leaving group: OSO₂CH₃I Br Cl NCS.

5. Indirect mutagenicity, through metabolic activation of the olefinic bond (by addition of S9 mix to the tester medium), can be ruled out for practically all compounds, the only exception found being 2,3-dichloro-1-propene where an increase of mutagenicity is encountered after addition of S9 mix; mechanistic explanations for this exception are provided.

6. Analogous activation is demonstrated for benzyl halides, the alkylating potency of which is even higher than that of genuine allylic compounds.

7. A variety of methyl- and chlorine-substituted allyl compounds has been included in the study: both groups increase activity, either by +I (CH₃) or by + M effects (Cl).

8. α,β-Unsaturated carbonyl compounds, e.g. acrolein and crotonaldehyde, also display direct mutagenic activity which is due to a completely different mechanism: covalent binding to nucleophilic sites of DNA bases by Michael addition. Methyl and other alkyl substitutions decrease the mutagenic potential in this type of compound. The corresponding alcohols, also displaying mutagenic activity but to a lesser degree, are metabolically activated by ADH (alcohol dehydrogenase) of the tester strain microbes to the aldehydes or ketones.