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

A symmetrical macrocyclic dizinc­(II) complex (1) has
been synthesized by using the ligand (L1) [μ-11,24-dimethyl-4,7,16,19-tetraoxa-3,8,15,20-tetraazatricyclo-[20.3.1.110,13] 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-[1.114,18] 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 (L2), 1,3-diamino
propane (L3), 1,4-diamino butane (L4), 1,2-diamino
benzene (L5), and 1,8-diamino naphthalene (L6). The ligand L1 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 × 105 to 9.50 × 105 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 (kobs) of 4.42
± 0.2 h–1, which shows a 108-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 L1, dizinc­(II) complexes 1, 3, and 6 showed cytotoxicity in human hepatoma HepG2
cancer cells, giving IC50 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.