Issue 7, 2010

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 (Ea = 30.0 kcal mol−1) are in excellent agreement with DFT calculations of the cyclization/rearrangement to diradical and cyclopentapyrazine carbene intermediates (Ea = 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.

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

Supplementary files

Article information

Article type
Communication
Submitted
02 Dec 2009
Accepted
03 Feb 2010
First published
15 Feb 2010

Org. Biomol. Chem., 2010,8, 1535-1539

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

C. Laroche, J. Li, C. Gonzales, W. M. David and S. M. Kerwin, Org. Biomol. Chem., 2010, 8, 1535 DOI: 10.1039/B925261D

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