The alkylating potential of -propiolactone (BPL), -butyrolactone (BBL), γ-butyrolactone, and δ-valerolactone, which can be formed by the in vivo nitrosation of primary amino acids, was investigated kinetically. The nucleophile NBP, 4-(p-nitrobenzyl)pyridine, a trap for alkylating agents, was used as an alkylation substrate. The alkylation reactions were performed under mimicked cellular conditions at neutral pH in water/dioxane solvent mixtures. To gain insight into the effect of the hydrolysis of lactones on their alkylating efficiency, alkylation and competing hydrolysis were studied in parallel. Conclusions were drawn as follows: (i) γ-Butyrolactone and δ-valerolactone afford neither appreciable NBP alkylation nor hydrolysis reactions; (ii) the alkylating potential of BPL is 10-fold higher than that of BBL, the reactivity of both being essentially enthalpy-controlled; (iii) a correlation was found between the alkylating potential of lactones and their carcinogenicity; (iv) the hydrolysis of lactones is not sufficiently effective to prevent alkylation; (v) the efficiency of alkylation, expressed as the alkylation rate/ hydrolysis rate ratio, decreases strongly with increasing amounts of dioxane in the reaction media; (vi) the absorption coefficients of the NBP-lactone adducts are as follows: NBP-BPL ) 5101 ( 111 M -1 cm -1 (λ ) 584 nm) and NBP-BBL ) 462 ( 19 M -1 cm -1 (λ ) 586 nm), the pronounced difference between these values being rationalized in terms of the adducts' structure; and (vii) linear correlations exist between the adducts' absorption coefficients and the water/dioxane ratio in the reaction media.
Since α-angelicalactone (AAL) substantially inhibits the formation of tumors, here its chemical reactivity was compared with that of carcinogenic lactones. Investigation of the electrophilic potential of AAL was carried out by studying the capacity of this lactone to form adducts with NBP, 4-( p-nitrobenzyl)pyridine, a substrate with nucleophilic characteristics similar to DNA bases. The formation of the AAL-NBP adduct occurs about 900,000-fold faster than with β-propiolactone, the most effective carcinogenic lactone ( G # 35 =52 and 87 kJ mol −1 , respectively). A stopped-flow technique was required for this reaction to be monitored. It was concluded that the formation of AAL-NBP adducts takes place through an entropy-straincatalyzed mechanism caused by early lactone ring cleavage. The kinetic results are consistent with the AAL potential as a chemoprotective agent. C 2007 Wiley Periodicals, Inc. Int J Chem
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