The (Z)-hex-1,5-diyne-3-ene reactive core common to the enediyne antitumor
antibiotics undergoes a Bergman cyclization after proper activation to afford reactive diradical intermediates that are responsible for initiating DNA cleavage. Direct modification of the enediyne core has been proposed as a method to permit
cancer cell-specific triggering of the diradical-generating cyclization. For example, 3-aza-3-ene-1,5-diynes undergo an aza-Bergman cyclization to afford the fleeting 2,5-didehydropyridine diradicals. While protonation of these aza-
enediynes can afford products of diradical trapping, the hydrolytic instability of the 3-aza-3-ene-1,5-diyne moiety prevents its use in pH-triggered
DNA cleaving
anticancer agents. Recently, more hydrolytically stable systems incorporating the 4-aza-3-ene-1,6-diyne moiety were developed. We report here studies of the 4-aza-3-ene-1,6-diyne-containing benzimidazolium
salt AZB002 [1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium tetrafluoroborate] and two structurally related heterocycles that lack the aza-enediyne functionality, AZB016 [1,3-dimethyl-2-(phenylethynyl)-3H-benzimidazolium triflate] and AZB004 [3-methyl-2-(phenylethynyl)benzothiazolium triflate]. The interaction of these compounds with
supercoiled DNA, a
double-stranded DNA fragment, and a short
DNA duplex
oligonucleotide was investigated. There are three distinct
DNA interactions exhibited by
AZB002: a frank strand scission leading to the relaxation of
supercoiled DNA and formation of at least two different
DNA adducts, one of which leads to
cytosine-specific cleavage after
piperidine/heat treatment. In contrast, analogues lacking the aza-enediyne functionality either fail to interact with
DNA (AZB016) or cleave
DNA at
guanine residues, presumably through alkylation of the N-7 position (AZB004). We also investigated the cytotoxicity of
AZB002 and the related
heterocyclic compounds AZB004 and AZB016 and find that only the
DNA interactive compounds
AZB002 and AZB004 display significant cytotoxicity. In particular,
AZB002 is cytotoxic against a wide range of
cancer cell lines.