title: 2-Alkynyl-N-propargyl pyridinium salts: pyridinium-based heterocyclic skipped aza-enediynes that cleave DNA by deoxyribosyl hydrogen-atom abstraction and guanine oxidation.
abstract: Diradical-generating cyclizations such as the enediyne Bergman cyclization and the enyne allene Myers-Saito cyclization have been exploited by nature in the mechanism of DNA cleavage by a series of potent antitumor antibiotics. Alternative diradical-generating cyclizations have been proposed in the design of selective antitumor agents; however, little information is available concerning the utility of these alternative cyclizations in radical-based DNA cleavage chemistry. One such alternative diradical-generating cyclization, the aza-Myers-Saito cyclization of aza-enyne allenes that are derived from base-promoted isomerization of skipped aza-enediynes, has been recently reported. Here, we report the synthesis and DNA cleavage chemistry of a series of pyridinium skipped aza-enediynes (2-alkynyl-N-propargyl pyridinium salts). Efficient DNA cleavage requires the presence of the skipped aza-enediyne functionality, and optimal DNA cleavage occurs at basic pH. Within this series of compounds, the analogue bearing a p-methoxyphenyl group on the pyridinium 2-alkyne substituents was found to be the most effective DNA cleavage agent, displaying significant supercoiled DNA-nicking activity at concentrations as low as 1 microM. Detailed studies of this analogue show that DNA cleavage occurs through 4'-hydrogen-atom abstraction from the DNA backbone and oxidation of guanine bases. This is the first report of enediyne-like radical-based DNA cleavage by an agent designed to undergo an alternative diradical-generating cyclization.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Bodin
authors.initials: B
authors.lastname: Tuesuwan
authors.forename: Sean M
authors.initials: SM
authors.lastname: Kerwin
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D017931:DNA Primers; D006147:Guanine / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D009019:Morphinans / Q000737:chemistry*; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D017931:DNA Primers; D006571:Heterocyclic Compounds; D009019:Morphinans; C440369:N-propargyl; D011726:Pyridinium Compounds; D006147:Guanine; D006859:Hydrogen; D004247:DNA