Please confirm you are human (Sign Up for free to never see this)
← Back to Search
Reaction Kinetics And Biological Action In Barley Of Mono-functional Methanesulfonic Esters.
Published 1970 · Biology
Abstract 1. As a background for studies of the action mechanisms of biological alkylating agents a number of methanesulfonic esters were investigated with respect to rates of hydrolysis and reaction with different nucleophiles, mostly at 20°, 25° and 37°. 2. The reaction patterns of monofunctional alkylating agents (AA) of the kind studied were characterized in terms of (a) reaction mechanism (S N 1 or S N 2); (b) the S wain -S cott (61,64) substrate constant s describing the dependence of bimolecular rate constant on nucleophilicity n of the receptor molecule; (c) the absolute reaction rates and their temperature dependence which are accurately described by activation energy E A (≈ activation enthalpy, Δ H *) and activation entropy Δ S *, the latter parameter giving, in addition, information about the reaction mechanism. 3. In the series of unsubstituted alkyl esters studied, which mostly react according to S N 2, branching on the α-carbon, as in iPMS, gives predominantly S N 1 type reaction. The strong steric hindrance of S N 2 reaction provoked by β-branching, as in iBMS and NeoMS, leads to the appearance of an S N 1 type behaviour at low n , e.g. in hydrolysis. Of substituents studied, β-hydroxy and β-methoxy decrease reactivity, without considerable influence on s . β-Positioned carbonyl gives very high values of s (i.e. gives a character of “SH inhibitors”) to the compounds, with a strong retardation of reaction rate at low n . In certain cases abnormally high rates of reaction with the hydroxyl ion are encountered. Thus β-OH (as in HOEMS) leads to 1,2-epoxide formation in rapid OH − catalyzed reaction; β-carbonyl compounds exhibit a strongly OH − dependent hydrolysis. 4. In barley kernels the toxic action of the AA is in most instances reconcilable with alkylation at n ≈ 5·1, which corresponds to cysteine ester at pH 7, whereas genetic effects apparently are caused by alkylation of centres with n = 2·5–3, corresponding to primary phosphate and DNA. Kernels are therefore presumably killed by protein alkylation, e.g. leading to enzyme inactivation, whereas mutation (including sterility) is probably induced by DNA alkylation. Exceptions are the α-branched esters, indicated to kill by genetic mechanisms, and β-branched esters which are also more toxic than expected from kinetic data, however, for unknown reasons. iPMS (low s ) induces mutation in a linear function of dose, whereas EMS and other esters of medium s exhibit an exponential dose response curve, possibly through simultaneous alkylation of DNA and protein, e.g. impairing repair enzyme function. The slight sterility induced by β-carbonyl esters implies that protein alkylation alone may provoke a certain genetic damage. 5. Experiments imply that, for a deeper understanding of the biological action of AA, the following factors should also be considered: (a) secondary reactions after alkylation of, e.g. DNA (especially important for chromosomal aberrations) and protein; (b) lipid/water partition; (c) steric factors on the side of AA as well as the receptor molecule.