Molybdenum(ii) complexes with p-substituted BIAN ligands: synthesis, characterization, biological activity and computational study.

New complexes [Mo(η3-C3H5)X(CO)2(4-Y-BIAN)] (4-Y-BIAN = bis(4-Y-phenyl)-acenaphthenequinonediimine), with X = Br and Y = H, Me, OMe, COOH and X = Cl, Y = OMe, as well as the cation with X = NCMe and Y = OMe were synthesized, expanding the scope of this family. Two single crystal X-ray structures (X = Br, Y = Me, OMe) display a less symmetric arrangement (axial isomer), where one N donor atom is trans to the allyl group and the second to one CO. DFT studies showed similar energies for the two possible isomers of the complexes, with a very small preference for the observed axial isomer. The HOMO of the complexes is localized in the metal and the HOMO-1 of the oxidized species has a contribution from the BIAN ligand, while the LUMO is fully localized in BIAN. Electrochemical studies showed one process corresponding to the oxidation of Mo(ii) to Mo(iii) for complexes with X = Br, Y = H, Me, and two oxidation reactions for those with X = Br, Y = Cl, OMe, while the COOH derivative exhibited no oxidation wave. The antitumor effect of the complexes with X = Br was tested in cancer lines, and the H and OMe complexes were particularly active, with EC50 values below 8 µM in HeLa cell lines. The DNA binding constants determined by titration experiments were comparable with those of doxorubicin and ethidium bromide, suggesting a mechanism of action based on intercalation in DNA.

Group 11 complexes with amino acid derivatives: Synthesis and antitumoral studies.

Gold(I), gold(III), silver(I) and copper(I) complexes with modified amino acid esters and phosphine ligands have been prepared in order to test their cytotoxic activity. Two different phosphine fragments, PPh3 and PPh2py (py=pyridine), have been used. The amino acid esters have been modified by introducing an aromatic amine as pyridine that coordinates metal fragments through the nitrogen atom, giving complexes of the type [M(L)(PR3)](+) or [AuCl3(L)] (L=l-valine-N-(4-pyridylcarbonyl) methyl ester (L1), l-alanine-N-(4-pyridylcarbonyl) methyl ester (L2), l-phenylalanine-N-(4-pyridylcarbonyl) methyl-ester) (L3); M=Au(I), Ag(I), Cu(I), PR3=PPh3, PPh2py). The in vitro cytotoxic activity of metal complexes was tested against four tumor human cell lines and one tumor mouse cell line. A metabolic activity test (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT) was used and IC50 values were compared with those obtained for cisplatin. Several complexes displayed significant cytotoxic activities. In order to determine whether antiproliferation and cell death are associated with apoptosis, NIH-3T3 cells were exposed to five selected complexes (Annexin V+ FITC, PI) and analyzed by flow cytometry. These experiments showed that the mechanism by which the complexes inhibit cell proliferation inducing cell death in NIH-3T3 cells is mainly apoptotic.

Strong inhibition of thioredoxin reductase by highly cytotoxic gold(I) complexes. DNA binding studies.

Biological properties of a series of aminophosphine-thiolate gold(I) complexes [Au(SR)(PPh2NHpy)] [Ph2PNHpy=2-(diphenylphosphinoamino)pyridine; HSR=2-mercaptopyridine (2-HSpy) (3), 2-mercaptonicotinic acid (2-H2-mna) (4), 2-thiouracil (2-HTU) (5) or 2-thiocytosine (2-HTC) (6)] and [Au(SR){PPh2NH(Htrz)}] [Ph2PNH(Htrz)=3-(diphenylphosphinoamino)-1,2,4-triazole]; HSR=2-mercaptopyridine (2-HSpy) (7), 2-thiocytosine (2-HTC) (8) or 6-thioguanine (6-HTG) (9) have been studied. Their antitumor properties have been tested in vitro against two tumor human cell lines, HeLa (derived from cervical cancer) and MCF-7 (derived from breast cancer), using a metabolic activity test (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT). Some of them showed excellent cytotoxic activity. With the aim to obtain more information about the mechanisms of action of these derivatives, the interactions of complexes 3, 5, 7 and 9 with thioredoxin reductase in HeLa cells were studied. They showed a potent inhibition of thioredoxin reductase activity. In order to complete this study, interactions of the complexes with calf thymus (CT-) DNA and with different bacterial DNAs, namely the plasmid pEMBL9 and the promoter region of the furA (ferric uptake regulator A) gene from Anabaena sp. PCC 7120 were investigated. Although interactions of complexes with CT-DNA have been verified, none of them cause significant changes in its structure.

Conjugates of ferrocene with biological compounds. Coordination to gold complexes and antitumoral properties.

Several bioconjugates of ferrocene with biological compounds such as aminoacid esters and related species have been prepared by reaction of chlorocarbonyl ferrocene with the corresponding amino acid ester (histidine methyl ester, tryptophan methyl ester, methionine methyl ester and lysine ethyl ester) or histamine or prolinamide in the presence of NEt(3). The reaction of the tryptophan or prolinamide ferrocene conjugates with [Au(acac)(PR(3))] (acac=acetylacetonate) results in the substitution of the proton of the cyclic NH groups by the fragment AuPR(3)(+) affording the complexes [Au(FcCO-tryptophan-OMe)(PR(3))] or [Au(FcCO-prolinamide)(PR(3))] (Fc=ferrocenyl group). The reaction of FcCO-Met-OMe with [Au(OTf)(PR(3))] (OTF=trifluoromethysulfonate) or [Au(C(6)F(5))(3)(OEt(2))] yields the gold(I) or gold(III) derivatives [Au(FcCO-Met-OMe)(PR(3))]OTf or [Au(C(6)F(5))(3)(FcCO-Met-OMe)], respectively. Cytotoxicity studies towards several cancer lines such as MCF-7, HeLa or NIE-115 have been performed. The ferrocene bioconjugates show no activity whereas the gold complexes exhibit antiproliferative effect. Preliminary studies of interaction of compounds with cells were carried out with the goal of increasing our knowledge on the mechanism of action of these potential drugs.

Mo(II) complexes: a new family of cytotoxic agents?

Several molybdenum complexes, [Mo(η(3)-C(3)H(5))X(CO)(2)(N-N)] (N-N = 1,10-phenanthroline, phen: X = CF(3)SO(3)T1, X = Br B1, X = Cl C1; N-N = 2,2'-bipyridyl, X = CF(3)SO(3)T2, X = Br B2) and [W(η(3)-C(3)H(5))Br(CO)(2)(phen)] (W1) have been synthesized and characterized. Their antitumor properties have been tested in vitro against human cancer cell lines cervical carcinoma (HeLa) and breast carcinoma (MCF-7) using a metabolic activity test (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT), leading to IC(50) values ranging from 3 to 45 µM, approximately. Most complexes exhibited significant antitumoral activity. Complexes B1 and T2 were chosen for subsequent studies aiming to understand their mechanism of action. Cellular uptake of molybdenum and octanol/water partition assays revealed that both B1 and T2 exhibit a selective uptake by cells and intermediate partition coefficients. The binding constants of B1 and T2 with ct DNA, as determined by absorption titration, are 2.08 (± 0.98) × 10(5) and 3.68 (± 2.01)x 10(5)M(-1), respectively. These results suggest that they interact with DNA changing its conformation and possibly inducing cell death, and may therefore provide a valuable tool in cancer chemotherapy.