Alkylation of DNA by endogenous and exogenous compounds is significant in the etiology of mutagenicity and genotoxicity.  Alkyl methanesulfonates display well-established mutagenic potentials in Salmonella typhimurium testing, as well as genotoxicity via the SOS chromotest.  Levels of mutagenic potential compare favorably with experimental SN1 reactivities of these alkylating agents.  In this investigation ab initio computations at Hartree-Fock and Density Functional Theory levels have been used to develop a QSAR model for experimental mutagenicities and genotoxicities for a series of alkyl methanesulfonates based on computed molecular properties associated with the carbocation intermediates, such as enthalpy of formation from the methanesulfonate esters, LUMO energies, charge distributions, cLogP, etc.  In general, the relation of mutagenic potential and carbocation stability/reactivity shows bifurcate behavior.  Mutagenic activity rises with increasing carbocation stability for primary and some secondary alkyl sulfonates.  Mutagenic potential then falls for methanesulfonates yielding more stabilized carbocations, presumably due to more rapid hydrolysis before alkylation of the nucleotide bases.

Modeling of mutagenicity and genotoxicity of alkyl methanesulfonates – a theoretical investigation

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.