title: A free energy approach to the prediction of olefin and epoxide mutagenicity and carcinogenicity.
abstract: 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 (ΔG(rxn)) were computed for each epoxide in the series. This study finds that an aqueous solution ΔG(rxn) threshold value of approximately -14.7 kcal/mol can be used to discern mutagenic/carcinogenic epoxides (ΔG(rxn) < -14.7 kcal/mol) from nonmutagens/noncarcinogens (ΔG(rxn) > -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.
authors.affiliation: Center for Green Chemistry and Green Engineering, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States. jakub.kostal@yale.edu
authors.forename: Jakub
authors.initials: J
authors.lastname: Kostal
authors.forename: Adelina
authors.initials: A
authors.lastname: Voutchkova-Kostal
authors.forename: Brian
authors.initials: B
authors.lastname: Weeks
authors.forename: Julie B
authors.initials: JB
authors.lastname: Zimmerman
authors.forename: Paul T
authors.initials: PT
authors.lastname: Anastas
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000633:toxicity*; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D004852:Epoxy Compounds / Q000737:chemistry / Q000633:toxicity*; D006219:Halogens / Q000737:chemistry; D008954:Models, Biological; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000475:Alkenes; D002273:Carcinogens; D004852:Epoxy Compounds; D006219:Halogens; D009153:Mutagens