title: Synthesis and enhanced DNA cleavage activities of bis-tacnorthoamide derivatives.
abstract: A new metal-free DNA cleaving reagent, bis-tacnorthoamide derivative 1 with two tacnorthoamide (tacnoa) units linked by a spacer containing anthraquinone, has been synthesized from triazatricyclo[5.2.1.0(4,10)]decane and characterized by NMR and mass spectrometry. For comparison, the corresponding compounds mono-tacnorthoamide derivative 2 with one tacnorthoamide unit and 6 with two tacnorthoamide units linked by an alkyl (1,6-hexamethylene) spacer without anthraquinone have also been synthesized. The DNA-binding property investigated via fluorescence and CD spectroscopy suggests that compounds 1 and 2 have an intercalating DNA binding mode, and the apparent binding constants of 1, 2 and 6 are 1.3 × 10(7) M(-1), 0.8 × 10(7) M(-1) and 8 × 10(5) M(-1), respectively. Agarose gel electrophoresis was used to assess plasmid pUC19 DNA cleavage activity promoted by 1, 2, 6 and parent tacnoa under physiological conditions, which gives rate constants k(obs) of 0.2126 ± 0.0055 h(-1), 0.0620 ± 0.0024 h(-1), 0.040 ± 0.0007 h(-1) and 0.0043 ± 0.0002 h(-1), respectively. The 50-fold and 15-fold rate acceleration over parent tacnoa is because of the anthraquinone moiety of compound 1 or 2 intercalating into DNA base pairs via a stacking interaction. Moreover, DNA cleavage reactions promoted by compound 1 give 5.3-fold rate acceleration over compound 6, which further demonstrates that the introduction of anthraquinone results in a large enhancement of DNA cleavage activity. In particular, DNA cleavage activity promoted by 1 bearing two tacnoa units is 3.3 times more effective than 2 bearing one tacnoa unit and the DNA cleavage by compound 1 was achieved effectively at a relatively low concentration (0.03 mM). This dramatic rate acceleration suggests the cooperative catalysis of the two positively charged tacnoa units in compound 1. The radical scavenger inhibition study and ESI-MS analysis of bis(2,4-dinitrophenyl) phosphate (BDNPP) and adenylyl(3'-5')phosphoadenine (APA) cleavage in the presence of compound 1 suggest the cleavage mechanism would be via a hydrolysis pathway by cleaving the phosphodiester bond of DNA.
authors.affiliation: Department of Chemistry, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, Jiangsu, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Wei
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Hu
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Lu
mesh_terms: D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D053837:DNA Cleavage; D004587:Electrophoresis, Agar Gel; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry*; D048289:Imidazolidines / Q000138:chemical synthesis / Q000737:chemistry*; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D010755:Organophosphates / Q000737:chemistry; D013050:Spectrometry, Fluorescence
chemical_list: D000880:Anthraquinones; D006575:Heterocyclic Compounds, 3-Ring; D048289:Imidazolidines; D007364:Intercalating Agents; D010755:Organophosphates; C546103:bis(2,4-dinitrophenyl) phosphate; D004247:DNA