Synthesis and enhanced DNA cleavage activities of bis-tacnorthoamide derivativesElectronic supplementary information (ESI) available: Spectra for all new compounds, agarose gel electrophoretogram, and kinetic data. See DOI: 10.1039/c2ob25743b

• Main Authors: Wei, Li, Shao, Ying, Zhou, Mi, Hu, Hong-Wen, Lu, Guo-Yuan
• Format: Journal Article
• Language: English
• Published: 10.10.2012
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c2ob25743b

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. A novel efficient metal-free DNA cleaving reagent, a bis-tacnorthoamide derivative, with two tacnorthoamide units linked by a spacer containing anthraquinone has been synthesized.