Chiral and Achiral Macrocyclic Copper(II) Complexes: Synthesis, Characterization, and Comparative Binding Studies with Calf-Thymus DNA

The binding mode and affinity of isoeuxanthone (1,6-dihydroxyxanthone) (1) and its piperidinyl derivative (1-hydroxy-6-(2-(1-piperidinyl)ethoxy)xanthone) (2) with calf thymus DNA were studied using absorption spectroscopy, fluorescence spectroscopy, circular dichroism (CD) spectroscopy and viscosity measurements. Results indicate that the two xanthones can intercalate into the DNA base pairs by the plane of xanthone ring and the binding affinity of the piperidinylethoxy substituted xanthone 2 is stronger than 1. In addition, the cytotoxic effects of both compounds were evaluated with the human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using acid phosphatase assay. Analyses show that the piperidinylethoxy substituted xanthone exhibits more effective cytotoxic activity than isoeuxanthone against the two cancer cells. The effects on the inhibition of tumor cells in vitro agree with the studies of DNAbinding.

Section: )supporting

confidence: 84%

Antitumor Activity and DNA-Binding Investigations of Isoeuxanthone and Its Piperidinyl Derivative

Wang

Wei

Yan

et al. 2013

“…Furthermore, the large decrease in intensity of the DNA helicity band indicates that the DNA is unwound upon interaction with the compounds and then transformed into other conformations. [36][37][38] The result is in agreement with structure changes concluded from absorbance spectra changes process of DNA upon adding the two compounds. Viscosity Studies Optical photophysical probes generally provide necessary, but not sufficient clues to support a binding mode.…”

Section: Resultssupporting

confidence: 87%

Cytotoxic Activity and DNA-Binding Investigations of Two Benzoxanthone Derivatives

Wang

Shen

Jia

et al. 2009

Natural products play a major role in anticancer drug discovery as a unique source of original structures which can provide models for future drug design. Xanthone compounds, secondary metabolites from higher plants and microorganisms, have very diverse biological profiles including anti-hypertensive, anti-oxidative, anti-thrombotic, and anticancer activity, based on their diverse structures.1-7) During the past several years, the xanthone template has generated a growing interest in the search for new antitumor agents. 8)The preliminary work has highlighted the high potentials of xanthones as a promising building motif for the development of a new class of potent anticancer drugs.Numerous biological experiments have demonstrated that DNA is one of the primary intracellular targets of anti-cancer drugs due to the interaction of small molecules with DNA, which cause DNA damage in cancer cells, block the division of cancer cells and result in cell death. 9) Up to now, few systematic studies of the interaction of xanthones and their derivatives with DNA have been reported. [10][11][12] However, their structure-activity relationships remain unestablished in the xanthones system. Benzoxanthones having four extended and conjugated fused rings may be viewed as flavone derivatives in which the phenyl group is fused with two aromatic rings. The structural features inherent in benzoxanthones, makes us aware that the conjugated p-systems in benzoxanthones may contribute significantly to the biological activity. The primary aim of this work was to gain some insight into the effect of structural factor in benzoxanthones on the probable binding mode and binding affinity toward DNA.In this work, the binding mode on the interactions of two benzoxanthones 1,3-dihydroxy-12H-benzo[b]xanthen-12-one (1) and 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (2) (shown in Fig. 1) with DNA was investigated by different kinds of spectrophotometric methods and viscosity measurements. The studies suggest that intercalative binding mode appears to be acceptable. In addition, the benzoxanthones were evaluated for cytotoxic activities toward human cervical cancer cell line (HeLa), human hepatocellular liver carcinoma cell (HepG2) and human normal liver cell line (L02) by acid phosphatase assay. ExperimentalMaterials The benzoxanthones 1 and 2 were prepared according to the literatures [13][14][15] with some improvement. Calf thymus DNA (ct DNA) and ethidium bromide (EB) were obtained from Sigma Chemical Co. All the measurements were carried out in doubly distilled water buffer containing 5 mM Tris and 50 mM NaCl, and adjusted to pH 7.4 with hydrochloric acid. The concentration of DNA solution was determined from UV absorption at 260 nm using a molar absorption coefficient e 260 ϭ6600 mol Ϫ1 cm Ϫ1. Purity of the DNA was checked by monitoring the ratio of the absorbance at 260 nm to that at 280 nm. The solution gave a ratio of A 260 /A 280 Ͼ1.80, indicating that DNA was sufficiently free from protein. 16,17)Physical Measurements The UV-Vis absorption ...

“…These observations are supportive of the intercalative mode of binding of the complexes, where in the stacking of the complex molecules between the base pairs of DNA leads to an enhancement in the positive band and the partial unwinding of the helix is reflected in the decreased intensity of the negative band, which attributed to a strong conformational change in DNA helix. 43,44) It is similar to that observed for [Ru(NH 3 ) 4 (qdppz)] 2ϩ and [Co(NH 3 ) 6 ] 3ϩ bound to DNA of short lengths with 160 base pairs. 45,46) The results obtained here validate those obtained from the UV-Vis spectral studies.…”

Section: )supporting

confidence: 81%

Synthesis, Characterization, Cytotoxic Activities, and DNA-Binding Studies of Ternary Copper(II) Complexes with New Coumarin Derivatives

Jia

et al. 2010

In this study, two novel complexes [Cu(MCVH)phen(H 2 O)] · ClO 4 (1) and [Cu(MCLH)phen(H 2 O)] · ClO 4 (2)(here, MCVH 2 ‫-7(؍‬hydroxy-4-methyl-8-coumarinyl) valine, MCLH 2 ‫-7(؍‬hydroxy-4-methyl-8-coumarinyl) leucine) have been synthesized and characterized by elemental analyses, molar conductance, infrared spectra (IR), 1 H-NMR and UV-Vis measurements. The interactions of them with calf thymus DNA (ct DNA) have been investigated by absorption spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy and viscosity measurements. Experimental results reveal an intercalative interaction with DNA for the complexes, furthermore the binding affinity of 2 is higher than that of 1 according to the calculated binding constant values. In addition, they were evaluated for their cytotoxic activities toward human prostate cancer cell (PC3), human liver cell (L02) and human myeloid leukemia cancer cell (HL-60) by acid phosphoatase assay. Both of them showed significant cytotoxic potency.Key words copper(II) complex; coumarin derivative; DNA-binding; intercalative mode; cytotoxic activity Chem. Pharm. Bull. 58(8) 1003-1008 (2010) © 2010 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: tangn@lzu.edu.cn; wangqin329@yahoo.com.cn concentrations of 1 and 2 as constant at 10 mM while varying the concentration of ct DNA. Fitting was completed using an Origin 6.0 spreadsheet, where values of the binding constants K b were calculated.Fluorescence spectra of the competitive binding experiments were carried out by maintaining the EB and ct DNA concentration at 3 mM and 30 mM, respectively, while increasing the concentrations of the complexes. Fitting was completed using an Origin 6.0 spreadsheet, where values of K q were calculated.Viscosity experiments were carried out on an Ubbelodhe viscometer, immersed in a thermostated water-bath maintained at 25.0Ϯ0.1°C. Titrations were performed for the complexes (1-5 mM), and each compound was introduced into DNA solution (50 mM) present in the viscometer. Flow time was measured with a digital stopwatch and each sample was measured three times and an average flow time was calculated.The CD spectra of DNA were recorded on a Jasco J-810 spectropolarimeter at 25.0Ϯ0.1°C. Calf thymus DNA used were 120 mM in concentration and compounds solutions was added to a ratio of 1 : 1 (DNA/compound). Each sample solution was scanned in the range of 200-350 nm. CD spectrum was generated which represented the average of three scans from which the buffer background had been subtracted.Acid Phosphoatase Assay The reagent, p-nitrophenyl phosphate (p-NPP), was obtained from Amresco. The compounds synthesized were dissolved in dimethyl sulphoxide (DMSO) and diluted in culture medium. The final concentration of DMSO in cultures was always not exceeding 0.5% (v/v), which did not cause toxicity. The PC3 and HL-60 cells obtained from ATCC were maintained in Dulbecco's modified Eagle's medium (DMEM) medium with 10% fetal bovine serum (FBS), 100 U/ml penicillin and 10...