Synthesis and Biological Evaluation of Xanthone Derivatives as Anti-Cancer Agents Targeting Topoisomerase II and DNA

Topoisomerase is one of the most important targets of anticancer drugs. In order to develop effective and low-toxic topoisomerase inhibitors, a series of xanthone derivatives have been designed and synthesized using the principles of skeleton transition. In vitro growth inhibition experiments of human breast cancer(MCF-7), gastric cancer (MGC-803), and cervical cancer(Hela) cell lines were used to evaluate the compound's anti-tumor cell proliferation activity. Most of the compounds showed anti-tumor growth activity, and also showed low toxicity to human normal cells L929. In the enzyme activity inhibition experiment, compounds 7d and 8d showed the best inhibitory activity. The DNA binding studies disclosed that the most potent compounds 7d and 8d can intercalate into DNA, induce apoptosis in MGC-803 cells and arrested at G2/M phase. Molecular docking showed that compounds 7d and 8d could bind with topoisomerase II and DNA through hydrogen bonds and π-stacking interactions.

DNA-Binding and Cytotoxicity of Copper(I) Complexes Containing Functionalized Dipyridylphenazine Ligands

A set of copper(I) coordination compounds with general formula [CuBr(PPh3)(dppz-R)] (dppz-R = dipyrido[3,2-a:2’,3’-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2’,3’-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2’,3’-c]phenazine (Cu-3), dipyrido[3,2-a:2’,3’-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2’,3’-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, 1H-NMR and 31P-NMR spectroscopies as well as mass spectrometry. The structure of Cu-1 was confirmed by X-ray crystallography. The effect of incorporating different functional groups on the dppz ligand on the binding into CT-DNA was evaluated by absorption spectroscopy, fluorescence quenching of EtBr-DNA adducts, and viscosity measurements. The functional groups affected the binding modes and hence the strength of binding affinities, as suggested by the changes in the relative viscosity. The differences in the quenching constants (Ksv) obtained from the fluorescence quenching assay highlight the importance of the functional groups in altering the binding sites on the DNA. The molecular docking data support the DNA-binding studies, with the sites and mode of interactions against B-DNA changing with the different functional groups. Evaluation of the anticancer activities of the five copper compounds against two different cancer cell lines (M-14 and MCF-7) indicated the importance of the functional groups on the dppz ligand on the anticancer activities. Among the five copper complexes, the cyano-containing complex (Cu-3) has the best anticancer activities.

A Novel Organometallic Rhenium Salt: DNA-Binding and Cytotoxicity Studies on Pancreatic, Breast and Lymphoma Cancers

DNA-binding studies of a variety of rhenium(I) tricarbonyl complexes are known. Primarily the rhenium complexes bind to DNA through intercalation or minor groove or both. We synthesized a novel organometallic salt of the type, [Re(µ-H)Re]+[Re(µ-OR)3Re]-. The UV-vis and emission spectroscopic titrations and viscosity studies indicate that the salt binds to DNA through partial intercalation. A variety of mono-, di-, and trinuclear rhenium(I) carbonyl complexes are known to exhibit cytotoxicity against numerous cancer cell lines. Examples of the cytotoxicity of tetranuclear rhenium (I) tricarbonyl complexes are rare. We have found that the tetranuclear, novel organometallic salt is highly potent on numerous cancer cells. The IC50 values (concentrations required to induce 50% cell deaths) are 0.220 µM on BxPC-3 pancreatic cancer cells, 0.298 µM on estrogen receptor positive MCF-7 breast cancer cells, 0.948 µM on triple negative MDA-MB-231 breast cancer cells, and 0.300 µM on U-937 lymphoma cells.

The Interaction Efficiency of XPD-p44 With Bulky DNA Damages Depends on the Structure of the Damage

The successful elimination of bulky DNA damages via the nucleotide excision repair (NER) system is largely determined by the damage recognition step. This step consists of primary recognition and verification of the damage. The TFIIH helicase XPD plays a key role in the verification step during NER. To date, the mechanism of damage verification is not sufficiently understood and requires further detailed research. This study is a systematic investigation of the interaction of ctXPD (Chaetomium thermophilum) as well as ctXPD-ctp44 with model DNAs, which contain structurally different bulky lesions with previously estimated NER repair efficiencies. We have used ATPase and DNA binding studies to assess the interaction of ctXPD with damaged DNA. The result of the analysis of ctXPD-ctp44 binding to DNA containing fluorescent and photoactivatable lesions demonstrates the relationship between the affinity of XPD for DNAs containing bulky damages and the ability of the NER system to eliminate the damage. Photo-cross-linking of ctXPD with DNA probes containing repairable and unrepairable photoactivatable damages reveals differences in the DNA interaction efficiency in the presence and absence of ctp44. In general, the results obtained indicate the ability of ctXPD-ctp44 to interact with a damage and suggest a significant role for ctp44 subunit in the verification process.