Synthesis, DNA‐Binding, Cleavage, and Cytotoxic Activity of New 1,7‐Dioxa‐4,10‐diazacyclododecane Artificial Receptors Containing Bisguanidinoethyl or Diaminoethyl Double Side Arms

Abstract

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.

Effect of the central metal ion on the cleavage of DNA by [M(TPA)Cl]ClO4 complexes (M=CoII, CuII and ZnII, TPA=tris(2-pyridylmethyl)amine): An efficient artificial nuclease for DNA cleavage

“…Interestingly the obtained hydrolysis rate enhancement by complex 1 shows very high nuclease activity. The pseudo Michaelis-Menten kinetic parameters k cat and K M for artificial nucleases for DNA cleavage that produced an enhancement rate of 10 6 -fold greater than the non-catalyzed ds DNA cleavage are collected in Table 3 These data reveal that the reported values of k cat and K M for different metal ions and metal complexes range from 40 to 0.04 h À1 and from 3.9 Â 10 À6 to 1.3 Â 10 À3 M, respectively [21,[36][37][38]41,[50][51][52][53][54][55][56][57][58][59]. Inspection of the available literature data for DNA cleavage by metal ions and by metal complexes clearly shows that complex 1 is considered to be one of the most efficient artificial nuclease for DNA cleavage; third most efficient catalyst.…”

Design of artificial nucleases and studies of their interaction with DNA

“…Our research group [29] Spectroscopic measurement showed that they hydrolyze the phosphodiester bond of DNA via "bifunctional cooperative catalysis", similar to SNase. In the first place, one guanidinium identifies and binds the phosphodiester bond in DNA by hydrogen bonding and electrostatic interaction, and helps the Cu(Ⅱ) center to bind the phosphodiester bond better (A).…”

Nucleic Acid and Phosphoester Hydrolytic Cleavage Catalysed by Aza-Crown Ether Metal Complexes as Synthetic Nucleases

“…Although lanthanide metal ion complexes can catalyse the hydrolytic cleavage of nucleic acids effectively, they have the disadvantage that these metal ions are not bio-elements per se, therefore, such systems are cytotoxic, and can be used only in vitro [7]. Many studies have been reported that the phosphate diester bond can be cleaved by many transition metal ions complexes via the hydrolytic pathway [22,37 -41], such as those of Cu(II) [40,41], and Zn(II) [22,38,39]. In general, the Lewis acidities of binuclear metal complexes are stronger than those of mononuclear metal complexes, so the binuclear metal complexes can activate nucleophilic species, promote the departure of the leaving group, and stabilise the transition-state intermediate via the synergistic effect of the bimetal centre effectively.…”