Synthesis, DNA-Binding, cleavage, and cytotoxic activity of new 1,7-dioxa-4,10-diazacyclododecane artificial receptors containing bisguanidinoethyl or diaminoethyl double side arms

作者：Sheng, Xin; Lu, Xiao-Min; Chen, Yue-Ting; Lu, Guo-Yuan^*; Zhang, Jing-Jing; Shao, Ying; Liu, Fang; Xu, Qiang

来源：Chemistry - A European Journal, 2007, 13(34): 9703-9712.

DOI：10.1002/chem.200700549

• copper
• crown ethers
• DNA cleavage
• metalloenzymes
• reaction mechanisms
• receptors

Novel 1,7-dioxa-4,10-diazacyclododecane artificial receptors with two pendant aminoethyl (3) or guanidinoethyl (4) side arms have been synthesized. Spectroscopy, including fluorescence and CD spectroscopy, of the interactions of 3, 4, and their copper(11) complexes with calf thymus DNA indicated that the DNA binding affinity of these compounds follows the order Cu2+-4 > Cu2+-3 > 4 > 3, and the binding constants of Cu2+-3 are Cu2+-4 are 7.2 x 10(4) and 8.7 x 10(4) M-1, respectively. Assessment by agarose gel electrophoresis of the plasmid pUC19 DNA cleavage activity in the presence of the receptors showed that the complexes Cu2+-3 and Cu2+-4 exhibit powerful supercoiled DNA cleavage efficiency. Kinetic data of DNA cleavage promoted by Cu2+-3 and Cu2+-4 under physiological conditions fit to a saturation kinetic profile with k(max) values of 0.865 and 0.596 h(-1), respectively, which give about 10(8)-fold rate acceleration over uncatalyzed supercoiled DNA. This acceleration is due to efficient cooperative catalysis of the copper(II) center and the functional (diamino or bisguanidinium) groups. In-vitro cytotoxic activities toward murine melanoma B16 cells and human leukemia HL-60 cells were also examined: Cu2+-4 shows the highest activitv with IG(50) values of 1.62x 10(-4) and 1.19 x 10(-5)M respectively.

• 单位
  现代配位化学国家重点实验室; 医药生物技术国家重点实验室; 南京大学