Advances in copper complexes as anticancer agents.

A mononuclear copper(II) complex based on the polypyridyl ligand 2,4,6-tris(2-pyridyl)-1,3,5-triazine (tptz), [Cu(tptz)2]2+: X-ray crystal structure, DNA binding and in vitro cell cytotoxicity

A series of macrobicyclic dizinc(II) complexes [Zn2L1–2B](ClO4)4 (1–6) have been synthesized and characterized (L1–2 are polyaza macrobicyclic binucleating ligands, and B is the N,N-donor heterocyclic base (viz. 2,2′-bipyridine (bipy) and 1,10-phenanthroline (phen)). The DNA and protein binding, DNA hydrolysis and anticancer activity of these complexes were investigated. The interactions of complexes 1–6 with calf thymus DNA were studied by spectroscopic techniques, including absorption, fluorescence and CD spectroscopy. The DNA binding constant values of the complexes were found to range from 2.80 × 105 to 5.25 × 105 M−1, and the binding affinities are in the following order: 3 > 6 > 2 > 5 > 1 > 4. All the dizinc(II) complexes 1–6 are found to effectively promote the hydrolytic cleavage of plasmid pBR322 DNA under anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 3 and 6 under physiological conditions give observed rate constants (kobs) of 5.56 ± 0.1 and 5.12 ± 0.2 h−1, respectively, showing a 107-fold rate acceleration over the uncatalyzed reaction of dsDNA. Remarkably, the macrobicyclic dizinc(II) complexes 1–6 bind and cleave bovine serum albumin (BSA), and effectively promote the caspase-3 and caspase-9 dependent deaths of HeLa and BeWo cancer cells. The cytotoxicity of the complexes was further confirmed by lactate dehydrogenase enzyme levels in cancer cell lysate and content media.

DNA targeting polyaza macrobicyclic dizinc(II) complexes promoting high in vitro caspase dependent anti-proliferative activity against human carcinoma cancer cells

Two novel copper-2,2′-bipyridine complexes [Cu(SAL)(2,2′-bipy)ClO4]2 (1) and [Cu(μ2-O)(2,2′-bipy)NO3]2 (2) (HSAL = salicylaldehyde) were synthesized and characterized by X-ray single-crystal diffraction, elemental analysis and IR spectra. The interactions of the complexes with salmon sperm DNA were investigated by viscosity analysis, UV, fluorescence and circular dichroism (CD) spectroscopic techniques. Absorption spectral (Kb = 3.00 × 105 M−1 (1), 3.49 × 105 M−1(2)), emission spectral ((Ksv) 3.33 × 104 M−1 (1), 3.40 × 104 M−1 (2)), and viscosity measurements reveal that 1 and 2 interact with DNA through intercalation. In fluorimetric studies, the enthalpy (ΔH > 0) and entropy (ΔS > 0) changes of the reactions between the Cu (II) complexes with DNA demonstrate hydrophobic interactions. In addition, CD study indicates the Cu (II) complexes cause a more B-like to a more A-like conformational change upon binding DNA. All the experimental results show that the interaction mode of the two complexes was greatly affected by the coordination environments of Cu (II) centers. Their in vitro cytotoxicity towards five selected tumor cell lines HepG-2, HeLa, NCI-H460, MCF-7 and HL-60 has been evaluated by MTT method, and 2 exhibits higher growth inhibition of the selected cell lines at concentration of 50 μM, this result is identical with their DNA binding ability order.

Two novel copper complexes of 2,2'-bipyridine: evaluation of the DNA binding and cytotoxic activity.

By inhibiting only two or three of 12 restriction enzymes, the series of [M(phen)(edda)] complexes [M(II) is Cu, Co, Zn; phen is 1,10-phenanthroline; edda is N,N′-ethylenediaminediacetate] exhibit DNA binding specificity. The Cu(II) and Zn(II) complexes could differentiate the palindromic sequences 5′-CATATG-3′ and 5′-GTATAC-3′, whereas the Co(II) analogue could not. This and other differences in their biological properties may arise from distinct differences in their octahedral structures. The complexes could inhibit topoisomerase I, stabilize or destabilize G-quadruplex, and lower the mitochondrial membrane potential of MCF7 breast cells. The pronounced stabilization of G-quadruplex by the Zn(II) complex may account for the additional ability of only the Zn(II) complex to induce cell cycle arrest in S phase. On the basis of the known action of anticancer compounds against the above-mentioned individual targets, we suggest the mode of action of the present complexes could involve multiple targets. Cytotoxicity studies with MCF10A and cisplatin-resistant MCF7 suggest that these complexes exhibit selectivity towards breast cancer cells over normal ones.

DNA molecular recognition and cellular selectivity of anticancer metal(II) complexes of ethylenediaminediacetate and phenanthroline: multiple targets.

In this study, the interactions of different groups substituted xanthone derivatives with calf thymus DNA (ct DNA) have been investigated by spectrophotometric methods and viscosity measurements. Results indicate that xanthone derivatives can intercalate into the DNA base pairs by the plane of xanthone ring and the various substituents may influence the binding affinity with DNA according to the calculated quenching constant values and the melting temperature of DNA. Furthermore, three tumor cell lines including esophagus squamous cancer cell line (ECA109), stomach cancer cell line (SGC7901) and lung cancer cell line (GLC-82) have been used to evaluate the cytotoxic activities of xanthone derivatives by MTT (microculture tetrazolium) method. Analysis show that the oxiranylmethoxy or piperidinylethoxy substituted xanthones exhibit more effective cytotoxic activity against three cancer cells than the other substituted xanthones. The effects on the inhibition of tumor cells in vitro agree with the studies of DNA-binding.

Cytotoxic Activity and DNA-binding Properties of Xanthone Derivatives

1, 8-(3, 6, 9-Trioxaundecane-1, 11-diyldioxy)xanthone (L), and its new Cu (II) complex [Cu·L·(CH3CN)2](ClO4)2 have been synthesized and characterized by 1H NMR, electrospray mass spectra (ESI-MS), elemental analyses, infrared spectra (IR) and X-ray single crystal diffraction. The crystal structure of complex shows that Cu (II) ion is encapsulated within the macrocycle of L. The geometry around copper is a distorted square bipyramid with two acetonitrile molecules at axial position, and four macrocyclic oxygens including the carbonyl oxygen on the equatorial positions. The interaction of Cu (II) complex with calf thymus DNA (ct DNA) has been investigated by spectrophotometric titrations, ethidium bromide (EB) displacement experiments, circular dichroism (CD) spectra and viscosity measurements. Rresults indicate that Cu (II) complex can intercalate into the DNA base pairs by the plane of xanthone ring. Furthermore, the Cu (II) complex was tested against tumor cell lines including ECA109, SGC7901and GLC-82 by MTT (microculture tetrazolium) method. The studies of DNA-binding agree with the effects on the inhibition of tumor cells in vitro.

Rui Shen

Papers

Cytotoxic Activity and DNA-binding Properties of Xanthone Derivatives

Synthesis, Crystal Structure, DNA-binding Properties and Cytotoxic Activity of the Copper (II) Complex Involving Xanthone