Kong Wai Tan

Factors affecting nucleolytic efficiency of some ternary metal complexes with DNA binding and recognition domains. Crystal and molecular structure of Zn(phen)(edda)

The binding selectivity of the M(phen)(edda) (M=Cu, Co, Ni, Zn; phen=1,10-phenanthroline, edda=ethylenediaminediacetic acid) complexes towards ds(CG)(6), ds(AT)(6) and ds(CGCGAATTCGCG) B-form oligonucleotide duplexes were studied by CD spectroscopy and molecular modeling. The binding mode is intercalation and there is selectivity towards AT-sequence and stacking preference for A/A parallel or diagonal adjacent base steps in their intercalation. The nucleolytic properties of these complexes were investigated and the factors affecting the extent of cleavage were determined to be: concentration of complex, the nature of metal(II) ion, type of buffer, pH of buffer, incubation time, incubation temperature, and the presence of hydrogen peroxide or ascorbic acid as exogenous reagents. The fluorescence property of these complexes and its origin were also investigated. The crystal structure of the Zn(phen)(edda) complex is reported in which the zinc atom displays a distorted trans-N(4)O(2) octahedral geometry; the crystal packing features double layers of complex molecules held together by extensive hydrogen bonding that inter-digitate with adjacent double layers via pi...pi interactions between 1,10-phenanthroline residues. The structure is compared with that of the recently described copper(II) analogue and, with the latter, included in molecular modeling.

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP).

Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, (1)H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV-Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism.

Zinc (II) complex with a cationic Schiff base ligand: synthesis, characterization, and biological studies.

A cationic Schiff base ligand, TSB (L) and its Zn (II) complex (1) were synthesized and characterized by using CHN, (1)H-NMR, FT-IR, UV, LC-MS, and X-ray methods. Their ability to inhibit topoisomerase I, DNA cleavage activities, and cytotoxicity were studied. X-ray diffraction study shows that the mononuclear complex 1 is four coordinated with distorted tetrahedral geometry. The singly deprotonated Schiff base ligand L acts as a bidentate ON-donor ligand. Complexation of L increases the inhibitory strength on topoisomerase I activity. Complex 1 could fully inhibit topoisomerase I activity at 250 μM, while L did not show any inhibitory effect on topoisomerase I activity. In addition, L and complex 1 could cleave pBR322 DNA in a concentration and time dependent profile. Surprisingly, L has better DNA cleavage activity than complex 1. The cleavage of DNA by complex 1 is altered in the presence of hydrogen peroxide. Furthermore, L and complex 1 are mildly cytotoxic towards human ovarian cancer A2780 and hepatocellular carcinoma HepG2.

Synthesis, characterization and biological evaluation of cationic hydrazone copper complexes with diverse diimine co-ligands

Four new copper(II) complexes containing triphenylphosphonium conjugated salicylaldehyde-(4-fluorobenzhydrazone), (L) with the formulation [CuL]Cl(1), [Cu(phen)L]Cl(2), [Cu(bpy)L]Cl(3), [Cu(dmbpy)L]Cl(4), (where L = doubly deprotonated hydrazone; phen = 1,10′-phenanthroline; bpy = 2,2′-bipyridine; dmbpy = 5,5′-dimethyl-2,2′-bipyridine) have been synthesized. The compounds were characterized by spectroscopic methods and, in the case of crystalline products, by X-ray crystallography. The topoisomerase I (topo I) inhibition, DNA binding and cleavage activities and cytotoxicity of the compounds were studied. A DNA relaxation study demonstrated that all the copper complexes successfully inhibit topo I enzyme by binding to topo I as the preferred pathway. Complex 1 is the most active with starting inhibitory concentration ≈20 μM. The planarity of the tridentate hydrazone Schiff base ligand and the diimine co-ligands increase the binding affinity to DNA. The presence of the 1,10′-phenanthroline co-ligand in complex 2 induces plasmid DNA (pBR322) cleavage without exogenous agents. It is noteworthy that the addition of diimine co-ligands to the copper(II) complex enhanced the cytotoxicity of the compounds, especially against the human prostate adenocarcinoma cell line (PC-3). Complex 2 exhibits the highest activity against PC-3 with the IC50 value of 2.47 ± 0.37 μM. Annexin V/propidium iodide analysis showed that compound 1 induces apoptotic and necrotic cell death, whereas compound 2–4 work mainly through apoptosis.

Topoisomerase I inhibition and DNA cleavage by zinc, copper, and nickel derivatives of 2-[2-bromoethyliminomethyl]-4-[ethoxymethyl]phenol complexes exhibiting anti-proliferation and anti-metastasis activity.

Three transition metal derivatives (Zn, Cu, and Ni) of 2-[2-bromoethyliminomethyl]-4-[ethoxymethyl]phenol (L) were synthesized by the reaction of the metal salts with the Schiff base ligand in one pot. In the crystal structure of [Zn(L)Br], the Schiff base ligand binds to the metal center through its phenolate oxygen and imine nitrogen, and adopts a distorted tetrahedral geometry. These compounds were found to inhibit topoisomerase I (topo I) activity, induce DNA cleavage and show DNA binding activity. Moreover, these compounds were found to be cytotoxic towards several cancer cell lines (A2780, MCF-7, HT29, HepG2, A549, PC3, LNCaP) and prevent metastasis of PC3. Collectively, Cu(II) complex 2 shows superior activity relative to its Zn(II) and Ni(II) analogs.

5-Ethyl-5-methyl-4-phenyl-5H-1,2,4-triazol-3(4H)-thione.

The five-membered ring of the title compound Δ1-1,2,4-triazoline-5-thione, C11H13N3S, is almost planar (r.m.s. deviation = 0.009 Å); the phenyl ring is aligned at 84.6 (2)° with respect to the five-membered ring. The crystal studied was a racemic twin with an approximate 20% minor twin component. Weak intermolecular C—H⋯N hydrogen bonding is present in the crystal structure.

(4-Hydr­oxy-2-oxidobenzaldehyde thio­semicarbazonato-κ3O2,N1,S)(1,10-phenanthroline-κ2N,N′)zinc(II) dimethyl sulfoxide disolvate monohydrate

The ZnII atom in the title compound, [Zn(C8H7N3O2S)(C12H8N2)]·2C2H6OS·H2O, is N,N′-chelated by the N-heterocycle and N,O,S-chelated by the deprotonated Schiff base in a distorted square-pyramidal enviroment. Hydrogen bonds link the mononuclear molecule, the water and the dimethyl sulfoxide (DMSO) molecules into a linear chain motif. One DMSO molecule is disordered over two positions in respect of the S atom in an approximate 1:1 ratio.

Ternary and binary copper(II) complexes: synthesis, characterization, ROS-inductive, proteasome inhibitory, and anticancer properties

Abstract Three ternary copper(II) complexes, [Cu(phen)(L-phe)Cl]·2H2O, [Cu(phen)(L-leu)Cl]·4½H2O, and [Cu(phen)(L-tyr)Cl]·3H2O, and four binary copper(II) complexes, [Cu(phen)Cl2], Cu(L-phe)2·½H2O, Cu(L-leu)2·½H2O, and Cu(L-tyr)2·H2O (where phen = 110-phenanthroline, L-phe = L-phenylalanine, L-tyr = L-tyrosine, L-leu = L-leucine and Cl- = chloride), were synthesized and characterized by elemental analysis, spectroscopic techniques (FTIR, UV–visible, fluorescence spectroscopy), magnetic susceptibility, molar conductivity, and lipophilicity measurement. X-ray diffraction determination of a single crystal of [Cu(phen)(L-tyr)Cl] showed two independent molecules in the asymmetric unit, each with the same distorted square pyramidal geometry about copper(II). p-Nitrosodimethylaniline assay revealed that the three ternary complexes were better inducers of reactive oxygen species over time than binary complexes, CuCl2, and free ligands. All the copper(II) complexes in this series inhibited the three proteolytic activities in the order Trypsin-like > Caspase-like > Chymotrypsin-like. In terms of anticancer properties, the copper(II)-phen complexes had GI50 values of less than 4 μM against MCF-7, HepG2, CNE1 and A549 cancer cell lines, more potent than cisplatin.

Zinc, copper and nickel derivatives of 2-[2-bromoethyliminomethyl]phenol as topoisomerase inhibitors exhibiting anti-proliferative and anti-metastatic properties

Three transition metal derivatives of (2-[2-bromoethyliminomethyl]phenol), M[OC6H4CHNCH2CH2Br]2 (M is zinc, copper and nickel) along with Ni[OC6H4CHNCH2CH2]2(H2O)4·2Br, were found to inhibit topoisomerase I (topo I) activity, induce DNA cleavage and bind to calf thymus DNA. The compounds were found to be cytotoxic when tested against cancer cell lines (A2780, MCF-7, HT29, HepG2, A549, PC3, LNCaP), and were anti-invasive against PC3. The inhibitory strength of the metal complexes was higher than that of the organic compound. The neutral metal complexes were synthesized by the reaction of the metal acetates with the Schiff base ligand whereas the bromide salt was obtained upon recrystallization of the nickel derivative from water. In the crystal structure of this salt, the cyclized Schiff base ligand binds to the nickel atom through its nitrogen donor, the metal atom showing an all-trans octahedral geometry. The metal atom in Cu[OC6H4CHNCH2CH2Br]2 exists in a square-planar environment.

(2E)-1-(6-Chloro-2-methyl-4-phenyl-quinolin-3-yl)-3-phenyl-prop-2-en-1-one.

In the title compound, C25H18ClNO, the conformation about the C=C double bond is E. Significant twists are evident in the molecule, with the benzene ring forming a dihedral angle of 53.92 (11)° with the quinolinyl residue. Further, the chalcone residue is approximately perpendicular to the quinolinyl residue [Cq—Cq—Cc—Oc torsion angle = −104.5 (3)°, where q = quinolinyl and c = chalcone]. In the crystal, the presence of C—H⋯O and C—H⋯π interactions leads to supramolecular layers lying parallel to (02).