Synthesis, DNA-binding, cleavage, and cytotoxic activity of new 1,7-dioxa-4,10-diazacyclododecane artificial receptors containing bisguanidinoethyl or diaminoethyl double side arms.
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(II) complexes with calf thymus DNA indicated that the DNA binding affinity of these compounds follows the order Cu(2+)-4>Cu(2+)-3>4>3, and the binding constants of Cu(2+)-3 are Cu(2+)-4 are 7.2x10(4) and 8.7x10(4) M(-1), respectively. Assessment by agarose gel electrophoresis of the plasmid pUC 19 DNA cleavage activity in the presence of the receptors showed that the complexes Cu(2+)-3 and Cu(2+)-4 exhibit powerful supercoiled DNA cleavage efficiency. Kinetic data of DNA cleavage promoted by Cu(2+)-3 and Cu(2+)-4 under physiological conditions fit to a saturation kinetic profile with kmax 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: Cu(2+)-4 shows the highest activity with IC(50) values of 1.62x10(-4) and 1.19x10(-5) M, respectively.
Sheng
Xin
X
Department of Chemistry, State Key Laboratory of Coordination, Chemistry, Nanjing University, Nanjing, PR China.
Lu
Xiao-Min
XM
Chen
Yue-Ting
YT
Lu
Guo-Yuan
GY
Zhang
Jing-Jing
JJ
Shao
Ying
Y
Liu
Fang
F
Xu
Qiang
Q
D000586:Amination; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D019791:Guanidine / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure
C526638:1,7-dioxa-4,10-diazacyclododecane; D006573:Heterocyclic Compounds, 1-Ring; D004247:DNA; C427203:calf thymus DNA; D019791:Guanidine