posted on 2012-12-17, 00:00authored byJakub 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.