A Series of Oxyimine-Based Macrocyclic Dinuclear Zinc(II) Complexes Enhances Phosphate Ester Hydrolysis, DNA Binding, DNA Hydrolysis, and Lactate Dehydrogenase Inhibition and Induces Apoptosis

Abstract

A symmetrical macrocyclic dizinc(II) complex (1) has been synthesized by using the ligand (L(1)) [μ-11,24-dimethyl-4,7,16,19-tetraoxa-3,8,15,20-tetraazatricyclo-[20.3.1.1(10,13)] heptacosa-1(25),2,7,9,11,13(27),14,20,22(26),23-decaene-26,27-diol]. A series of unsymmetrical macrocyclic dizinc(II) complexes (2-6) has been synthesized by Schiff base condensation of bicompartmental mononuclear complex [ZnL] [μ-3,16-dimethyl-8,11-dioxa-7,12-diazadicyclo-[1.1(14,18)] heptacosa-1,3,5(20),6,12,14,16,18(19)-octacaene-19,20-diolato)zinc(II)] with various diamines like 1,2-diamino ethane (L(2)), 1,3-diamino propane (L(3)), 1,4-diamino butane (L(4)), 1,2-diamino benzene (L(5)), and 1,8-diamino naphthalene (L(6)). The ligand L(1) and all the zinc(II) complexes were structurally characterized. To corroborate the consequence of the aromatic moiety in comparison to the aliphatic moiety present in the macrocyclic ring on the phosphate ester hydrolysis, DNA binding and cleavage properties have been studied. The observed first order rate constant values for the hydrolysis of 4-nitrophenyl phosphate ester reaction are in the range from 2.73 × 10(-2) to 9.86 × 10(-2) s(-1).The interactions of complexes 1-6 with calf thymus DNA were studied by spectroscopic techniques, including absorption, fluorescence, and circular dichroism spectroscopy. The DNA binding constant values of the complexes were found in the range from 1.80 × 10(5) to 9.50 × 10(5) M(-1), and the binding affinities are in the following order: 6 > 5 > 1 > 2 > 3 > 4. All the dizinc(II) complexes 1-6 effectively promoted the hydrolytic cleavage of plasmid pBR322 DNA under anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 6 under physiological conditions give the observed rate constant (k(obs)) of 4.42 ± 0.2 h(-1), which shows a 10(8)-fold rate acceleration over the uncatalyzed reaction of ds-DNA. The comparison of the dizinc(II) complexes 1-6 with the monozinc(II) complex [ZnL] indicates that the DNA cleavage acceleration promoted by 1-6 are due to the efficient cooperative catalysis of the two close proximate zinc(II) cation centers. The ligand L(1), dizinc(II) complexes 1, 3, and 6 showed cytotoxicity in human hepatoma HepG2 cancer cells, giving IC(50) values of 117, 37.1, 16.5, and 8.32 μM, respectively. The results demonstrated that 6, a dizinc(II) complex with potent antiproliferative activity, is able to induce caspase-dependent apoptosis in human cancer cells. Cytotoxicity of the complexes was further confirmed by the lactate dehydrogenase enzyme level in HepG2 cell lysate and content media.

Phosphatase models: Synthesis, structure and catalytic activity of zinc complexes derived from a phenolic Mannich-base ligand

“…The coordination patterns and binding models of the catalystsubstrate complex have been largely explored in literature [15,16,20,30,42] and after rigorous considerations two plausible catalytic cycles having reasonably good agreement with our kinetic results have been postulated from the previous representative mechanisms. The substrate molecule binds as a dianionic mononitrophenyl phosphate to the complex having phosphatase activity.…”

“…Over the years, synthetic Zn(II) (and also other transition metal) complexes have been judiciously studied as phosphate ester models taking into account their extraordinary Lewis acidity, redox rigidity, nucleophile generation, leaving group stabilization and physiological relevancy [11,12]. However, among the numerous catalytically promiscuous Zn(II) derivatives [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] some complexes show low activity, others require rigorous synthetic conditions or have high toxicity. Therefore the development of new efficient metallocatalysts is still a tough challenge in the field of biocatalysis.…”

Synthesis, structural characterization and biological properties of Cu(II), Ni(II), Mn(II), Zn(II) and VO(II) complexes of tetradentate Schiff bases

“…Electrophoresis was performed at constant voltage (100 V) until the bromophenol blue reached to the ¾ of the gel. The gel was stained for 10 min by immersing in an ethidium bromide solution [19]. The gel was then destained for 10 min by keeping in sterilized distilled water and the plasmid bands visualized by photographing the gel under a UV Transilluminator.…”

Fluorescence sensor for sequential detection of zinc and phosphate ions

“…Zn 2+ ions are also an essential component of many enzymes, e.g., carbonic anhydrase, transcription factors, and zinc finger proteins, in which they play catalytic or structural roles [15]. Clinically, diverse Zn 2+ -based compounds have been used as tumor photosensitizers [16], antibacterial/antimicrobial and anticancer agents [17], radioprotective agents [18], and antidiabetic insulin mimetics [19]. Moreover, the hepato and cardio toxicity induced by some anticancer drugs can be reduced by Zn 2+ [20].…”