Ma Ángeles Martínez

DNA-cleavage induced by new macrocyclic Schiff base dinuclear Cu(I) complexes containing pyridyl pendant arms.

A new series of dinuclear Cu(I) complexes with hexaazamacrocyclic Schiff base ligand containing pyridyl pendant arms has been synthesized and characterized. The solid-state structures of [Cu(2)(I)(bsp3py)](CF(3)SO(3))(2) (1(CF(3)SO(3))(2)), [Cu(2)(I)(bsm3py)](SbF(6))(2) (2(SbF(6))(2)), and [Cu(2)(I)(bsp2py)](CF(3)SO(3))(2) (3(CF(3)SO(3))(2)) have been established by single-crystal X-ray diffraction analysis. The geometries of the copper centers in all three cases are almost identical showing a distorted tetrahedral coordination, very close to a trigonal pyramidal arrangement. Interactions of complexes with calf thymus DNA have been investigated by circular dichroism spectroscopy (CD) which suggests that the interaction for each complex is a nonintercalative mode with regard to DNA. The electrophoretic mobility study and the atomic force microscopy (AFM) in the presence of H(2)O(2) reveal a cleavage of pBR322 supercoiled DNA that depends on the nature of the Cu(I) complex used. The most efficient reactivity is observed for complexes 1(CF(3)SO(3))(2) and 2(CF(3)SO(3))(2) whereas complex 3(CF(3)SO(3))(2) displays a lesser reactivity. The different DNA-cleavage activity of complexes 1-3 is due the different electronic factors and complex topology induced by the natures of the different ligands. This work constitutes an example of how small modifications introduced in the macrocyclic backbone of the metal complexes lead to dramatic changes in the nuclease activity.

Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells.

Differential redox homeostasis in normal and malignant cells suggests that pro-oxidant-induced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a pro-oxidant deviation well-tolerated by nonmalignant cells might rapidly reach a cell-death threshold in malignant cells already at a high setpoint of constitutive oxidative stress. To test this hypothesis, we took advantage of a selected number of amine-pyridine-based Fe(II) complexes that operate as efficient and robust oxidation catalysts of organic substrates upon reaction with peroxides. Five of these Fe(II)-complexes and the corresponding aminopyridine ligands were selected to evaluate their anticancer properties. We found that the iron complexes failed to display any relevant activity, while the corresponding ligands exhibited significant antiproliferative activity. Among the ligands, none of which were hemolytic, compounds 1, 2 and 5 were cytotoxic in the low micromolar range against a panel of molecularly diverse human cancer cell lines. Importantly, the cytotoxic activity profile of some compounds remained unaltered in epithelial-to-mesenchymal (EMT)-induced stable populations of cancer stem-like cells, which acquired resistance to the well-known ROS inducer doxorubicin. Compounds 1, 2 and 5 inhibited the clonogenicity of cancer cells and induced apoptotic cell death accompanied by caspase 3/7 activation. Flow cytometry analyses indicated that ligands were strong inducers of oxidative stress, leading to a 7-fold increase in intracellular ROS levels. ROS induction was associated with their ability to bind intracellular iron and generate active coordination complexes inside of cells. In contrast, extracellular complexation of iron inhibited the activity of the ligands. Iron complexes showed a high proficiency to cleave DNA through oxidative-dependent mechanisms, suggesting a likely mechanism of cytotoxicity. In summary, we report that, upon chelation of intracellular iron, the pro-oxidant activity of amine-pyrimidine-based iron complexes efficiently kills cancer and cancer stem-like cells, thus providing functional evidence for an efficient family of redox-directed anti-cancer metallodrugs.

Ligand influence over the formation of dinuclear [2+2] versus trinuclear [3+3] Cu(I) Schiff base macrocyclic complexes.

The preparation and characterization of three new macrocyclic ligands with pendant arms based on the [2+2] condensation of isophthalaldehyde and the corresponding triamine substituted at the central N-atom is reported. None of these new macrocyclic ligands undergo any equilibrium reaction, based on imine hydrolysis to generate [1+1] macrocyclic formation or higher oligomeric compounds, such as [3+3], [4+4], etc., at least within the time scale of days. This indicates the stability of the newly generated imine bond. In sharp contrast, the reaction of the [2+2] macrocyclic Schiff bases with Cu(I) generates the corresponding dinuclear Cu(I) complexes [Cu(2)(L(1))](2+), 1(2+); [Cu(2)(L(2))(CH(3)CN)(2)](2+), 2(2+); and [Cu(2)(L(3))(CH(3)CN)(2)](2+), 3(2+), together with their trinuclear Cu(I) homologues [Cu(3)(L(4))](3+), 4(3+); [Cu(3)(L(5))(CH(3)CN)(3)](3+), 5(3+); and [Cu(3)(L(6))(CH(3)CN)(3)](3+), 6(3+), where the [2+2] ligand has undergone an expansion to the corresponding [3+3] Schiff base that is denoted as L(4), L(5), or L(6). The conditions under which the dinuclear and trinuclear complexes are formed were analyzed in terms of solvent dependence and synthetic pathways. The new complexes are characterized in solution by NMR, UV-vis, and MS spectroscopy and in the solid state by X-ray diffraction analysis and IR spectroscopy. For the particular case of the L(2) ligand, MS spectroscopy is also used to monitor the metal assisted transformation where the dinuclear complex 2(2+) is transformed into the trinuclear complex 5(3+). The Cu(I) complexes described here, in general, react slowly (within the time scale of days) with molecular oxygen, except for the ones containing the phenolic ligands 2(2+) and 5(3+) that react a bit faster.

A Systematic Evaluation of Molecular Recognition Phenomena. Part 5. Selective Binding of Tripolyphosphate and ATP to Isomeric Hexaazamacrocyclic Ligands Containing Xylylic Spacers

Protonation constants for 3,6,9,16,19,22-hexaazatricyclo[22.2.2.211,14]triaconta-1(27),11(30),12,14(29),24(28), 25-hexaene (P2) and 3,7,11,18,22,26-hexaazatricyclo[26.2.2.213,16]tetratriaconta-1(31),13(34),14,16(33),28(32),29-hexaene (P3) and their host–guest interactions with tripolyphosphate (Tr) and ATP (At) have been determined and evaluated by 1H NMR and potentiometric equilibrium methods. Ternary complexes were formed in aqueous solution as a result of hydrogen bond formation and Coulombic interactions between the host and the guest. For the case of ATP π-stacking interactions were found. Formation constants for all the species obtained are reported and compared with the isomeric 3,7,11,19,23,27-hexaazatricyclo[27.3.1.113,17]tetratriaconta-1(33),13,15,17(34),29,31-hexaene (Bn) and 3,6,9,17,20,23-hexaazatricyclo[23.3.1.111,15]triaconta-1(29),11,13,15(30), 25(27)-hexaene (Bd) ligands. Bonding interactions reach a maximum for H6P2Tr+, yielding a value of 12.02. The selectivity of the P3 and P2 ligands with regard to ATP and Tr substrates (S) is discussed and illustrated with global species distribution diagrams showing a strong preference for the latter over the former as a consequence of the much stronger formation constants with Tr. An analysis of the isomeric effect was also carried out by comparing the P3-S vs. Bn-S and P2-S vs. Bd-S systems. For the systems using Tr, a selectivity of more than 97% (pH 5.0) was achieved for its complexation when using the meta (Bd) rather than the para (P2) isomer, due solely to the size and shape of the receptors cavity. In the case of the P3 and Bn ligands the selectivity toward Tr complexation decreased to 85% (pH 8.0). Molecular recognition of tripolyphosphate and ATP is achieved through the formation of anionic complexes with isomeric hexaazamacrocyclic ligands. A selectivity of more than 97% is achieved for tripolyphosphate complexation when using the meta rather than the para isomer, a result due solely to the size and shape of the receptors cavity.

FeCl2py4+ catalyzed transformation of aromatic amines by HOOH under mild conditions

Abstract FeCl2py4+ is capable of activating HOOH for the selective and efficient (yields range roughly from 50 to 80%) transformation of anilines at room temperature using pyridine as the solvent. Initially, aniline yields mainly nitrosobenzene that in turn reacts with more aniline to form the corresponding azo and azoxybenzene derivatives. Replacing HOOH by t-BuOOH in the system, changes the product distribution dramatically forming only nitrobenzene. Under the same conditions FeCl2py4+ efficiently catalyzes the mono-demethylation of N,N′-dimethylaniline by HOOH.