title: DNA modification by 4-aza-3-ene-1,6-diynes: DNA cleavage, pH-dependent cytosine-specific interactions, and cancer cell cytotoxicity.
abstract: 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.
authors.affiliation: College of Pharmacy, University of Texas at Austin, PHR 4.220, Austin, Texas 78712-1074, USA.
authors.forename: Wirote
authors.initials: W
authors.lastname: Tuntiwechapikul
authors.forename: Wendi M
authors.initials: WM
authors.lastname: David
authors.forename: Dalip
authors.initials: D
authors.lastname: Kumar
authors.forename: Miguel
authors.initials: M
authors.lastname: Salazar
authors.forename: Sean M
authors.initials: SM
authors.lastname: Kerwin
mesh_terms: D000480:Alkynes / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D001372:Aza Compounds / Q000494:pharmacology* / Q000633:toxicity; D001562:Benzimidazoles / Q000494:pharmacology* / Q000633:toxicity; D052160:Benzothiazoles; D003596:Cytosine / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism*; D006131:Growth Inhibitors / Q000633:toxicity*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology / Q000633:toxicity; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D010880:Piperidines / Q000494:pharmacology / Q000633:toxicity; D013844:Thiazoles / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020298:U937 Cells / Q000187:drug effects
chemical_list: C522230:1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium; D000480:Alkynes; D000970:Antineoplastic Agents; D001372:Aza Compounds; D001562:Benzimidazoles; D052160:Benzothiazoles; D018736:DNA Adducts; D004278:DNA, Superhelical; D006131:Growth Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D010880:Piperidines; D013844:Thiazoles; C032727:piperidine; D003596:Cytosine; C005465:benzothiazole