Caifeng Bi

Cellular and computational studies of proteasome inhibition and apoptosis induction in human cancer cells by amino acid Schiff base–copper complexes

Proliferation and apoptosis pathways are tightly regulated in a cell by the ubiquitin-proteasome system (UPS) and alterations in the UPS may result in cellular transformation or other pathological conditions. Indeed, the proteasome is often found to be overactive in cancer cells. It has also been found that cancer cells are more sensitive to proteasome inhibition than normal cells, and therefore proteasome inhibitors are pursued as antitumor drugs. The use of the proteasome inhibitor Bortezomib for treatment of multiple myeloma and mantle cell lymphoma has proved this principle. Recent studies have suggested that copper complexes can inhibit proteasome activity and induce apoptosis in some human cancer cells. However, the involved molecular mechanism is unknown. In this study, we investigated the biological activities of four amino acid Schiff base-copper(II) complexes by using human breast (MDA-MB-231 and MCF-7) and prostate (PC-3) cancer cells. The complexes C1 and C3, but not their counterparts C2 and C4, inhibit the chymotrypsin-like activity of purified 20S proteasome and human cancer cellular 26S proteasome, cause accumulation of proteasome target proteins Bax and IκB-α, and induce growth inhibition and apoptosis in concentration- and time-dependent manners. Docking analysis shows that C1, but not C2 has hydrophobic, pi-pi, pi-cation and hydrogen bond interactions with the proteasomal chymotrypsin-like pocket and could stably fit into the S3 region, leading to specific inhibition. Our study has identified the mechanism of action of these copper complexes on inhibiting tumor cell proteasome and suggested their great potential as novel anticancer agents.

Syntheses, structural diversity and photocatalytic properties of various Co(II) coordination polymers based on a “V”-shaped 1,3-di(4′-carboxyl-phenyl)benzene acid and different imidazole bridging ligands

Four novel Co(II) coordination polymers (CPs) based on a “V”-shaped 1,3-di(4′-carboxyl-phenyl)benzene acid (H2dpb), namely {[Co2(dpb)2(4,4′-bibp)2]·2(CH3CN)}n (1), [Co(Hdpb)2(4,4′-bibp)]n (2), {[Co2(dpb)2(tib)2]·H2O}n (3) and {[Co(dpb)(bimb)0.5]·DMF·0.5(CH3CN)}n (4) (4,4′-bibp = 4,4′-bis(imidazol-1-yl)biphenyl, tib = 1,3,5-tris(1-imidazolyl)benzene and bimb = 1,4-bis(imidazol-1-ylmethyl)benzene), have been hydrothermally synthesized and characterized by elemental analysis, IR spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric (TG) analysis and single-crystal X-ray diffraction. Single-crystal X-ray diffraction analysis reveals that complex 1 possesses a uninodal 4-connected 3D (three-dimensional) cds topology framework with the Schlafli symbol (65·8). Complex 2 shows 1D zigzag chains, which are further assembled into a 3D supramolecular structure by O–H⋯O hydrogen bonds. Complex 3 shows an unprecedented 3-nodal (3,4,6)-connected 3D framework with the Schlafli symbol (62·7)2(64·75·84·9·10)(64·82), while complex 4 displays a {Co2(COO)4} binuclear SBU-based 3D 6-connected (44·611)-unprecedented framework. Moreover, the photocatalytic degradation of the four Co(II) compounds (complexes 1–4) has been investigated.

1,10-phenanthroline promotes copper complexes into tumor cells and induces apoptosis by inhibiting the proteasome activity

Indole-3-acetic acid and indole-3-propionic acid, two potent natural plant growth hormones, have attracted attention as promising prodrugs in cancer therapy. Copper is known to be a cofactor essential for tumor angiogenesis. We have previously reported that taurine, l-glutamine, and quinoline-2-carboxaldehyde Schiff base copper complexes inhibit cell proliferation and proteasome activity in human cancer cells. In the current study, we synthesized two types of copper complexes, dinuclear complexes and ternary complexes, to investigate whether a certain structure could easily carry copper into cancer cells and consequently inhibit tumor proteasome activity and induce apoptosis. We observed that ternary complexes binding with 1,10-phenanthroline are more potent proteasome inhibitors and apoptosis inducers than dinuclear complexes in PC-3 human prostate cancer cells. Furthermore, the ternary complexes potently inhibit proteasome activity before induction of apoptosis in MDA-MB-231 human breast cancer cells, but not in nontumorigenic MCF-10A cells. Our results suggest that copper complexes binding with 1,10-phenanthroline as the third ligand could serve as potent, selective proteasome inhibitors and apoptosis inducers in tumor cells, and that the ternary complexes may be good potential anticancer drugs.

Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells.

Although cadmium (Cd) is a widespread environmental contaminant and human carcinogen, our studies indicate an organic Cd complex to be a potent inhibitor of proteasomal chymotrypsin-like (CT-like) activity, further capable of inducing apoptosis in a cancer cell-specific manner. It has been reported that the ligands indole-3-butyric acid (L1) and indole-3-propionic acid (L2) have cancer-fighting effects when tested in a rat carcinoma model. In addition, 3, 5-diaminobenzoic acid o-vanillin Schiff bases (L3) have high antimicrobial activity and a large number of Schiff base complexes have been reported to have proteasome-inhibitory activity. We therefore hypothesized that synthetic forms of Cd in combination with L1, L2 and L3 may have proteasome-inhibitory and apoptosis-inducing activities, which would be cancer cell-specific. To test this hypothesis, we have synthesized three novel Cd-containing complexes: [Cd2(C12H12O2N)4(H2O)2]·2H2O (Cd1), [Cd2(C11H10O2N)4(H2O)2]·2H2O (Cd2) and [Cd(C7H4N2O2)(C8H6O2)2]·2H2O (Cd3), by using these three ligands. We sought out to characterize and assess the proteasome-inhibitory and anti-proliferative properties of these three Cd complexes in human breast cancer cells. Cd1, Cd2 and Cd3 were found to effectively inhibit the chymotrypsin-like activity of purified 20S proteasome with IC50 values of 2.6, 3.0 and 3.3 μΜ, respectively. Moreover, inhibition of cancer cell proliferation also correlated with this effect. As a result of proteasomal shutdown, the accumulation of ubiquitinated proteins and the proteasome target IκB-α protein as well as induction of apoptosis were observed. To account for the cancer specificity of this effect, immortalized, non-tumorigenic breast MCF10A cells were used under the same experimental conditions. Our results indicate that MCF10A cells are much less sensitive to the Cd1, Cd2 and Cd3 complexes when compared to MDA MB 231 breast cancer cells. Therefore, our study suggests that these Cd organic complexes are capable of inhibiting tumor cellular proteasome activity and consequently induce cancer cell-specific apoptotic death.

Synthesis, characterization, and antibacterial activity of new rare-earth ion complexes with unsymmetrical Schiff base ligand

A new unsymmetrical Schiff base ligand (H2LLi) was synthesized using L-lysine, salicylaldehyde, and 2-hydroxy-1-naphthaldehyde. Three rare-earth ion complexes of this ligand, [REE(H2L)(NO3)]NO3 · 2H2O (REE = La, Sm, Ho), have been prepared and characterized by elemental analyses, IR spectra, UV spectra, TG-DTG, and molar conductance. The antibacterial activity of the ligand and its complexes are also studied. The antibacterial experiments indicate that this ligand and its complexes possess antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis and the complexes have higher activity than that of the ligand.

Synthesis, crystal structure, and DNA interaction of magnesium(II) complexes with Schiff bases

A pair of stereoisomers of magnesium Schiff base complexes, [Mg(C18H16N3O2)2·2CH3OH] n (1) (C18H16N3O2: 2-acetylpyridine-l-tryptophan) and [Mg(C18H16N3O2)2·2CH3OH] n (2) (C18H16N3O2: 2-acetylpyridine-d-tryptophan), was synthesized and characterized by IR, UV, elemental analysis, 1H NMR, and X-ray diffraction single crystal analysis. The analyses of the structures indicate that they all crystallize in the tetragonal crystal system, space group P4 3 2 1 2 and P4 1 2 1 2, respectively. The two magnesium complexes have similar crystal structures. Mg(II) is six-coordinate with two nitrogens from C=N, two nitrogens from pyridine, and two carboxylic oxygens in different ligands forming a distorted octahedral geometry. Through N–H···O intermolecular hydrogen bonds a 2-D layer structure was formed. The interaction between 1 and calf thymus DNA was also investigated by UV absorption spectra, fluorescence emission spectra and viscometry. The results indicate that 1 interacts with DNA very strongly (K b = 2.01 × 107 L mol−1 and K sq = 0.195). The nature of the binding seems to be mainly an electrostatic interaction between DNA and the magnesium complex. Other binding modes, such as hydrogen bonds, may also exist.

Novel Polypyridyl chelators deplete cellular zinc and destabilize the X-linked inhibitor of apoptosis protein (XIAP) prior to induction of apoptosis in human prostate and breast cancer cells.

X‐linked inhibitor of apoptosis protein (XIAP), inhibits the initiation and execution phases of the apoptotic pathway. XIAP is the most potent member of the inhibitor of apoptosis protein (IAP) family of the endogenous caspase inhibitors. Therefore, targeting XIAP may be a promising strategy for the treatment of apoptosis‐resistant malignancies. In this study, we systematically studied the relationships of chemical structures of several novel ligands to their zinc (Zn)‐binding ability, molecular target XIAP, and tumor cell death‐inducing activity. We show that treatment of PC‐3 prostate cancer and MDA‐MB‐231 breast cancer cells with these membrane‐permeable Zn‐chelators with different Zn affinities results in varying degrees of XIAP depletion. Following decreased level of XIAP expression, we also show apoptosis‐related caspase activation and cellular morphological changes upon treatment with strong Zn‐chelators N4Py and BnTPEN. Addition of Zn has a full protective effect on the cells treated with these chelators, while iron (Fe) addition has only partial protection that, however, can be further increased to a comparable level of protection as Zn by inhibition of ROS generation, indicating that cell death effects mediated by Fe‐ but not Zn‐complexes involve redox cycling. These findings suggest that strong Zn‐chelating agents may be useful in the treatment of apoptosis‐resistant human cancers. J. Cell. Biochem. 113: 2567–2575, 2012.

Metal-based 2,3-indolinedione derivatives as proteasome inhibitors and inducers of apoptosis in human cancer cells

Proliferation and apoptotic pathways are tightly regulated in cells by the ubiquitin-proteasome system (UPS). Alterations in the UPS may result in cellular transformation or other pathological conditions. The proteasome is indeed often found to be overactive in cancer cells. It has been reported that 2,3-indolinedione (L), which exists in marine organisms, as well as in mammals, is a proteasome inhibitor. Studies have shown that metal-based complexes inhibit proteasome activity and induce apoptosis in certain human cancer cells. In the current study, we synthesized six novel metal-based complexes with derivatives of 2,3-indolinedione: [Cd (C15H11O3N2) (CH3COO)] (C1), [Cd (C15H11O2N2) (CH3COO)] (C2), [Co (C15H9O4N2) (CH3COO)] (C3), [Co (C15H11O2N2) (CH3COO)] (C4), [Zn (C19H14O3N3) (CH3COO)] (C5) and [Zn (C17H13O3N2) (CH3COO)] (C6). We sought to characterize and assess the proteasome inhibitory and anti-proliferative effects of these metal-based complexes in human breast (MDA-MB-231) and prostate (LNCaP and PC-3) cancer cells, in order to determine whether specific structures contribute to the inhibition of tumor proteasome activity and the induction of apoptosis. The results revealed that the complexes, C1, C3 and C5, but not their counterparts, C2, C4 and C6, inhibited the chymotrypsin-like activity of the human cancer cellular 26S proteasome; in addition, these complexes promoted the accumulation of the proteasome target protein, Bax, inhibited cell growth and induced apoptosis in a concentration- and time-dependent manner due to their unique structures. Our data suggest that the study of metal-based complexes, including aromatic ring structures with electron-attracting groups, may be an interesting research direction for the development of anticancer drugs.

Synthesis and crystal structure of a new nickel(II) coordination polymer based on Schiff base

A new Schiff base coordination polymer, [Ni(C18H16N3O2)2 · 2CH3OH]n (C18H16N3O2, 2-acetylpyridine-L-tryptophan), was synthesized and characterized by IR, UV, and X-ray diffraction singlecrystal analysis. The crystal crystallizes in the tetragonal crystal system, space group P43212 with cell parameters a = 11.8912(11), c = 28.822(3) Å, V = 4075.5(6) Å3, Z = 4, F(000) = 1544, S = 1.187, ρcalcd = 1.199 g cm−3, μ = 0.525 mm−1, the final R1 = 0.0515 and wR2 = 0.1513 for 3602 observed reflections (I > 2σ(I)). The Ni(II) atom is six-coordinated by two nitrogen atoms from C=N, two nitrogen atoms from pyridine rings and two carboxylic oxygen atoms in different ligands, forming a distorted octahedron geometry. Each ligand serves as a bridging ligand to link Ni2+ ions through carboxylic oxygen atoms, leading to a two-dimensional coordination polymer.

Structure and coordination environment of the zinc complex with vanillin of double-stranded helix

The structure and coordination environment of unusually double-stranded helix of complex [Zn(C8H7O3)2(H2O)2] are studied experimentally and by the density functional theory (DFT) method. The Zn2+ ion coordinates six oxygen atoms of deprotonated vanillin and water molecules forming an octahedron. The intermolecular hydrogen bonds and π interactions of the vanillin fragments contributed to the formation of the double-stranded helical supramolecular structure in the crystal. Counterpoise geometric parameters of the calculation agree with the crystal structure determined by experiment. The stabilization energy between the donor and acceptor obtained from an analysis of natural bond orbitals of the indicated six ligand oxygen atoms act as electron donor to Zn2+ ion. The results of the density functional theory on the complex demonstrate that the different coordinated oxygen atoms, which have different chemical environment, distort the coordination octahedron.