American Chemical Society
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A Free Energy Approach to the Prediction of Olefin and Epoxide Mutagenicity and Carcinogenicity

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journal contribution
posted on 2012-12-17, 00:00 authored by Jakub Kostal, Adelina Voutchkova-Kostal, Brian Weeks, Julie B. Zimmerman, Paul T. Anastas
The mutagenic and carcinogenic effects of strong alkylating agents, such as epoxides, have been attributed to their ability to covalently bind DNA in vivo. Most olefins are readily oxidized to reactive epoxides by CytP450. In an effort to develop predictive models for olefin and epoxide mutagenicity, the ring openings of 15 halogen-, alkyl-, alkenyl-, and aryl-substituted epoxides were modeled by quantum-mechanical transition state calculations using MP2/6-31+G­(d,p) in the gas phase and in aqueous solution. Free energies of activation (ΔG) and free energies of reaction (ΔGrxn) were computed for each epoxide in the series. This study finds that an aqueous solution ΔGrxn threshold value of approximately −14.7 kcal/mol can be used to discern mutagenic/carcinogenic epoxides (ΔGrxn < −14.7 kcal/mol) from nonmutagens/noncarcinogens (ΔGrxn > −14.7 kcal/mol). The computed reaction thermodynamics are appropriate regardless of ring-opening mechanism in vivo and are thus proposed as an effective in silico screen and design guideline for decreasing potential mutagenicity and carcinogenicity of olefins and their respective epoxides.