Cyclization kinetics and biological evaluation of an anticancer 1,2-dialkynylimidazole

Abstract

1,2-Dialkynylimidazoles have been reported to undergo thermal cyclization/rearrangement to diradical and carbene intermediates. Optimization of the synthesis of the 1,2-dialkynylimidazole 3 has provided sufficient material for kinetic and biological studies. The 1,2-dialkynylimidazole 3 is cytotoxic against a wide range of cancer cells and induces apoptosis in A549 cells. Experimentally-determined kinetics of the thermolysis of 3 (E_a = 30.0 kcal mol⁻¹) are in excellent agreement with DFT calculations of the cyclization/rearrangement to diradical and cyclopentapyrazine carbene intermediates (E_a = 29.7 kcal mol⁻¹). Commensurate with the relatively high barrier for cyclization of 3, no evidence for cleavage of supercoiled DNA under physiological conditions was found; however, under aqueous conditions at 70 °C 3 formed a covalent adduct with a model peptide. These studies indicate that if cyclization of 3 is involved in its anticancer activity, the cyclization must be facilitated, perhaps through initial protein binding, which could lead to covalent protein modification.