Review: recent advances and future development of metal complexes as anticancer agents

Since the initial discovery of applications of platinum complexes in the clinical treatment of many kinds of cancers, the efficiency of platinum complexes in inhibiting the proliferation of various types of tumors surprised researchers working on the development of anticancer drugs. Meanwhile, despite the potent clinical treatment patients get from platinum complexes, there are also disadvantages including limited solubility in aqueous media and side effects like ototoxicity, myelosuppression, nephrotoxicity, and poor selectivity toward healthy cells. For this reason, efforts have been made to search for novel solutions. Non-platinum complexes (like Fe, Pd, Ru, Cu, Bi, Zn, etc.) were found with potential anticancer activities. We here review the properties of five metal complexes as anticancer agents and make comparisons among them in biological features and cytotoxic activity. Seeking the interrelation between microstructure and mechanism of anticancer, we hope this review provides distinct insights into future study of anticancer agents.     

Carbohydrate-appended 2,2'-dipicolylamine metal complexes as potential imaging agents

Three discrete carbohydrate-appended 2,2'-dipicolylamine ligands were complexed to the {M(CO)(3)}(+) (M = (99m)Tc/Re) core: 2-(bis(2-pyridinylmethyl)amino)ethyl-beta-d-glucopyranoside (L(1)()), 2-(bis(2-pyridinylmethyl)amino)ethyl-beta-D-xylopyranoside (L(2)()), and 2-(bis(2-pyridinylmethyl)amino)ethyl-alpha-d-mannopyranoside (L(3)). An ethylene spacer is used to separate the carbohydrate moiety and the dipicolylamine (DPA) function in all three ligands. The Re complexes [Re(L(1-3))(CO)(3)]Br were characterized by (1)H and (13)C 1D/2D NMR spectroscopies, which confirmed the pendant nature of the carbohydrate moieties in solution. NMR measurements also established the long-range asymmetric effect of the carbohydrate functions on the chelating portion of the ligand. One analogue, [Re(L(1))(CO)(3)]Cl, was characterized in the solid state by X-ray crystallography. Further characterization was provided by IR spectroscopy, elemental analysis, conductivity, and mass spectrometry. Radiolabeling of L(1)-L(3) with [(99m)Tc(H(2)O)(3)(CO)(3)](+) afforded high yield compounds of identical character to the Re analogues. The radiolabeled compounds were found to be stable toward ligand exchange in the presence of a large excess of either cysteine or histidine over a 24-h period.     

Autocatalytic polymerization of selenium/polypyrrole nanocomposites as functional theranostic agents for multi-spectral photoacoustic imaging and photothermal therapy of tumor

The synchronization of diagnosis and treatment is a new trend in cancer treatment. Photoacoustic imaging (PAI) and photothermal therapy (PTT) are recognized as one of the perfect combinations. The autocatalytic polymerization of selenium/polypyrrole (Se@PPy) nanocomposites with a wide-absorption band at near-infrared region (NIR, 800 nm) has been developed in this paper. The wide optical absorption characteristics enable Se@PPy nanocomposites to achieve multi-spectral PAI. Ex vivo experiments show desirable photoacoustic ability of the Se@PPy nanocomposites at wavelengths ranging from 700 nm to 900 nm, which is better than that of commercial indocyanine green (ICG). Se@PPy nanocomposites have high photothermal conversion efficiency up to 36.3% as well as excellent photo-thermal stability. In vitro cytotoxicity test demonstrates that the Se@PPy nanocomposites have good bio-safety. Furthermore, the feasibility of Se@PPy nanocomposites for enhancing multi-spectral PAI guided PTT was verified on 4T1 tumor-bearing nude mice. Our results indicate that Se@PPy nanocomposites could be used as an effective theranostic agent for near-infrared light-mediated PAI and PTT of tumor.     

Transition metal complexes of a potential anticancer quinazoline ligand

A new heterocycle, namely 2-(furyl)-3-(furfuralimino)-1,2-dihydroquinazolin-4(3H)-one (ffdq) was formed by the condensation of 2-aminobenzoylhydrazide with furfural and characterized by physico-chemical, spectroscopic, and single crystal X-ray diffraction studies. A series of complexes of ffdq have been synthesized and characterized by physico-chemical, spectroscopic, and thermal studies. According to the i.r. and ¹H-n.m.r. spectra ffdq behaves as a bidentate ligand coordinating through quinazoline oxygen and azomethine nitrogen. The FAB-mass spectrum of the Cd(II) complex indicates the monomeric nature of this complex. The X-band e.p.r. spectrum of the Cu(II) complex and thermal stabilities of the Co(II) and Ni(II) complexes are discussed.     

Gating of single molecule transistors: combining field-effect and chemical control

Previously we have demonstrated that several structural features are crucial for the functionality of molecular field-effect transistors. The effect of additional structural aspects of molecular wires is explored. These include the type of, the thiol binding location on, and the chemical substitutions of a conjugated system. Pentacene, porphyrin, and the Tour-Reed devices are utilized as model systems. The thiol binding location is shown to have a varied effect on the transmission of a system depending on the molecular orbitals involved. Substitution by electron withdrawing and donating groups is illustrated to have a substantial effect on the transmission of single molecule devices. The substitution effect is either a simple energy shifting effect or a more complicated resonance effect, and can be used to effectively tune the electronic behavior of a single molecule field effect transistor.     

Paramagnetic lanthanide complexes as PARACEST agents for medical imaging

This tutorial review examines the fundamental aspects of a new class of contrast media for MRI based upon the chemical shift saturation transfer (CEST) mechanism. Several paramagnetic versions called PARACEST agents have shown utility as responsive agents for reporting physiological or metabolic information by MRI. It is shown that basic NMR exchange theory can be used to predict how parameters such as chemical shift, bound water lifetimes, and relaxation rates can be optimized to maximize the sensitivity of PARACEST agents.     

Some uses of transition metal complexes as anti-cancer and anti-HIV agents

The success of the clinical uses of cisplatin, cis-[Pt(II)(NH(3))(2)Cl(2)], has stimulated considerable interest in using other metal complexes as new therapeutic agents. This perspective describes our recent work on several classes of gold(III), platinum(II), ruthenium(II, III, IV), iron(II) and vanadium(IV) complexes for anti-cancer and anti-HIV treatments.     

Gold complexes with dithiothiophene ligands: a metal based on a neutral molecule

The gold complexes n-Bu4N[Au(alpha-tpdt)2] (5), n-Bu4N[Au(dtpdt)2] (4) and n-Bu4N[Au(tpdt)2] (6) based on new dithiothiophene ligands (alpha-tpdt= 2,3-thiophenedithiolate, dtpdt=2,3-dihydro-5,6-thiophenedithiolate and tpdt = 3,4-thiophenedithiolate) have been prepared and characterised. These gold(III) complexes are diamagnetic, but they can be oxidised with iodine to the paramagnetic compounds [Au(alpha-tpdt)2] (8), [Au(dtpdt)2] (7) and n-Bu4N[[Au(tpdt)2]n-2] (9), which were isolated as fine powders and which exhibit paramagnetic susceptibilities that are almost temperature independent with room temperature values of 2.5 x 10(-4), 2.0 x 10(-4) and 5 x 10(-4) emu x mol(-1), respectively. Interestingly, the neutral complex [Au(alpha-tpdt)2] (8) as a polycrystalline sample displays the properties of a metallic system with a room temperature electrical conductivity of 6 S x cm(-1) and a thermoelectric power of 5.5 microVK(-1); this is the first time that this metallic property has been observed in a molecular system based on a neutral species.     

Thiophenolato-bridged dinuclear arene ruthenium complexes: a new family of highly cytotoxic anticancer agents

New cationic diruthenium complexes of the type [(arene)(2)Ru(2)(SPh)(3)](+), arene being C(6)H(6), p-(i)PrC(6)H(4)Me, C(6)Me(6), C(6)H(5)R, where R = (CH(2))(n)OC(O)C(6)H(4)-p-O(CH(2))(6)CH(3) or (CH(2))(n)OC(O)CH=CHC(6)H(4)-p-OCH(3) and n = 2 or 4, are obtained from the reaction of the corresponding precursor [(arene)RuCl(2)](2) and thiophenol and isolated as their chloride salts. The complexes have been fully characterised by spectroscopic methods and the solid state structure of [(C(6)H(6))(2)Ru(2)(SPh)(3)](+), crystallised as the hexafluorophosphate salt, has been established by single crystal X-ray diffraction. The complexes are highly cytotoxic against human ovarian cancer cells (cell lines A2780 and A2780cisR), with the IC(50) values being in the submicromolar range. In comparison the analogous trishydroxythiophenolato compounds [(arene)(2)Ru(2)(S-p-C(6)H(4)OH)(3)]Cl (IC(50) values around 100 μM) are much less cytotoxic. Thus, it would appear that the increased antiproliferative effect of the arene ruthenium complexes is due to the presence of the phenyl or toluyl substituents at the three thiolato bridges.     

Metal-based anticancer agents: targeting androgen-dependent and androgen-independent prostate and COX-positive pancreatic cancer cells by phenanthrenequinone semicarbazone and its metal complexes

A planar, polycyclic and aromatic hydrocarbon ligand, namely 9,10-phenanthrenequinone semicarbazone, and its transition metal complexes have been synthesized and structurally characterized. The in vitro antiproliferative activity of these compounds against five human cancer cell lines revealed that they were effective against androgen receptor-positive/negative prostate cancer cells as well as COX-positive pancreatic BxPC-3 cancer cell line. The driving force behind such antiproliferative activity seems to be the up-regulated COX expression in these cells, which was amenable for targeting through metal complexation. These structural motifs can, therefore, serve as a starting point for developing novel cytotoxic agents against the growing number of prostate and pancreatic cancers.     

Polarographic studies of iron complexes as potential contrast as agents in magnetic resonance imaging

Iron(III) complexes of polyaminocarboxylic acids of potential use as contrast agents in magnetic resonance imaging wre investigated by differential pulse polarography. The complexes with diethylenetrinitrilopentaacetic acid, trans-1,2-cyclohexylenedinitrilotetraacetic acid and triethylenetetranitrilohexaacetic acid (TTHA) wre found to decompose slowly at pH 7.2. With TTHA, a mixture of 1:1 and 2:1 complexes was obtained, and the transformation between the two complexes was slow. Ethylenediimonobis[(2-hydroxyphenyl)acetic acid] (EHPG) was found to be the most suitable ligand. The complex formation is kinetically slow, and a special procedure for the preparation of the complex is required; the complex is then stable for one week at pH 7.2. The polarographic measuremeents are preferably made at pH 9.2, where a well-defined reduction peak is obtained. The complex is stable for 2 days at pH 9.2. At pH values below 9, a double peak is obtained, except for low concentrations of the complex. Both Fe(III)EHPG and Fe(II)EHPG adsorb at the mercury electrode. The polarographic determination can be done in the presence of 10% of urine or serum without interference. The detection limit is in the low μM range.     

Cell-specific, activatable, and theranostic prodrug for dual-targeted cancer imaging and therapy

Herein we describe the design and synthesis of a folate-doxorubicin conjugate with activatable fluorescence and activatable cytotoxicity. In this study we discovered that the cytotoxicity and fluorescence of doxorubicin are quenched (OFF) when covalently linked with folic acid. Most importantly, when the conjugate is designed with a disulfide bond linking the targeting folate unit and the cytotoxic doxorubicin, a targeted activatable prodrug is obtained that becomes activated (ON) within the cell by glutathione-mediated dissociation and nuclear translocation, showing enhanced fluorescence and cellular toxicity. In our novel design, folic acid acted as both a targeting ligand for the folate receptor as well as a quencher for doxorubicin's fluorescence.     

Lanthanide complexes as imaging agents anchored on nano-sized particles of boehmite

The synthesis of boehmite nanoparticles modified with lanthanides (Eu, Tb and Gd) is described. Their synthesis, characterization and in vitro assays with HeLa cells were performed. The nuclear magnetic relaxation dispersion (NMRD) profiles of the two chelating moieties were studied. Imaging data from laser scanning confocal fluorescence microscopy and flow cytometry revealed that the nanoscaffolds were taken up by the cells, distributed throughout the cytoplasm and showed no toxicity. This platform could represent an alternative to silica-based inert matrices as imaging vehicles.     

Isocytosine as a hydrogen-bonding partner and as a ligand in metal complexes

Isocytosine (ICH; 1) exists in solution in an equilibrium of tautomers 1a and 1b with the N1 and N3 positions carrying the acidic proton, respectively. In the solid state, both tautomers coexist in a 1:1 ratio. As we show, the N3H tautomer 1b can selectively be crystallized in the presence of the model nucleobase 1-methylcytosine (1-MeC). The complex 1b x (1-MeC)2 x H2O (2) forms pairs through three hydrogen bonds between the components; hydrogen bonds between identical molecules are also formed, leading to an infinite tape structure. On the other hand, the N1H tautomer 1a co-crystallizes with protonated ICH to give [1a x ICH2]NO3 (3), again with three hydrogen bonds between the partners, yet the acidic proton is disordered over the two entities. With M(II)(dien) (M=Pt, Pd; dien=diethylenetriamine) preferential coordination of tautomer 1a through the N3 position is observed. DFT calculations, which were also extended to Pt(II)(tmeda) linkage isomers (tmeda=N,N,N',N'-tetramethylethylenediamine), suggest that intramolecular hydrogen bonding between the ICH tautomers and the co-ligands at M, while adding to the preference for N3 coordination, is not the major determining factor. Rather it is the inherently stronger Pt-N3 bond which favors complexation of 1a. With an excess of M(II)(dien), dinuclear species [M2(dien)2(IC-N1,N3)]3+ (M=Pd(II), 4 and Pt(II), 5) also form and were isolated as their ClO4(-) salts and structurally characterized. In strongly acidic medium 5 is converted to [Pt(dien)(ICH-N1)]2+ (6), that is, to the Pt(II) complex of tautomer 1b.     

Luminescent zinc salen complexes as single and two-photon fluorescence subcellular imaging probes

A novel class of ZnSalens (ZnL(1-10)) with lipophilic and cationic conjugates as optical probes in single and two-photon fluorescence microscopy images of living cells were prepared, which exhibited chemo- and photostability, low cytotoxicity and high subcellular selectivity.     

Telomerase as a possible target for anticancer therapy

Telomeres, the termini of chromosomes, provide essential stability to linear eukaryotic chromosomes. The enzyme telomerase is one mechanism that maintains telomeres, and is activated in 85% of human cancer cells. New studies on peptide nucleic acids (PNAs) that inhibit telomerase have demonstrated that unexpected regions of the enzyme can serve as targets for inhibitors. The novel delivery method used expands the utility of PNAs.     

A comparative DFT study of some N-based aromatic ligand metal complexes as anticancer agents and analysis of their mode of interaction with DNA base pair

Metal complexed anticancer agents interact with DNA nucleobase pairs (AT and GC) through different types of binding mode such as intercalation, groove binding, covalent binding, etc. Minor and major groove binding mechanism of DNA base pair is the key factor for all kinds of anticancer agent; as metal complexes have a great affinity to bind with DNA nucleobase either through minor or major groove. Ligands in metal complexes also play a vital role during the interaction with DNA base pairs; these ligands directly interact with DNA through different interacting modes. Generally, anticancer agents with less sterically hindered N-based aromatic and planar ligands are the key component for DNA binding; as the structure of such ligands are quite compatible for following intercalation and groove binding mechanism. Since, the experimental investigation for drug-DNA nucleobase complexes are extremely complicated, therefore; quantum mechanical calculations might be very helpful for computing the actual interactions in drug-DNA complexes. Quantum mechanical approaches such as density functional theory (DFT) might be a very important and useful tool to investigate the actual mode of interaction of metal complexed antitumor agents with DNA nucleobase. Herein, we have taken some metal complexes with N-based aromatic ligands as antitumor agents to investigate the proper mode of interaction between drug-DNA complexes.