Marisa Belicchi Ferrari

Synthesis, characterization and X-ray structures of new antiproliferative and proapoptotic natural aldehyde thiosemicarbazones and their nickel(II) and copper(II) complexes

Synthesis and characterization of new thiosemicarbazones derived from natural aldehydes (1-9) have been investigated in order to develop a research program aimed at the development of compounds with antiviral, antibacterial, and antitumor properties. These substances contain both a chain with N and S nucleophilic centers with tuberculostatic activity, and an alkyl or terpenic moiety. In addition, a few nickel(II) and copper(II) complexes (10-18), derived also from the previously studied ligands, were synthesized and characterized by means of NMR and IR techniques. The trans-2-octenal N(1)-phenylthiosemicarbazone and its nickel complex were also characterized by X-ray diffractometry. Biological studies, performed with some of these compounds, have involved both inhibition of cell proliferation and apoptosis tests in vitro on human leukemia cell line U937 to deepen our knowledge on the way these substances interfere with biological processes in leukemic cells.

Synthesis, characterisation, X-ray structure and biological activity of three new 5-formyluracil thiosemicarbazone complexes.

Three new complexes of transition metals as copper, nickel and cobalt with 5-formyluracil thiosemicarbazone (H3ut) have been synthesised and characterised by single-crystal X-ray diffraction. In all compounds the ligand behaves as SNO terdentate. In the copper complex the coordination geometry is square pyramidal with the ligand lying on the basal plane and two water molecules that complete the metal environment, the nickel compound is surrounded by six donor atoms (three of the ligand, two water oxygen atoms and a chlorine atom) in an octahedral fashion, and cobalt also shows an octahedral geometry but determined only by two terdentate ligand molecules. These three compounds have been tested on human leukemic cell lines K562 and CEM. The nickel and cobalt complexes have demonstrated low activity in cell growth, while the copper complex that is more active has been tested also on a third leukemic human cell line (U937), but it was not able to induce apoptosis on all cell lines.

SYNTHESIS, SPECTROSCOPIC AND STRUCTURAL CHARACTERIZATION, AND BIOLOGICAL ACTIVITY OF AQUACHLORO(PYRIDOXAL THIOSEMICARBAZONE) COPPER(II) CHLORIDE

The synthesis, spectroscopic studies, x-ray crystal structure, and biological properties of the complex [Cu(H2L)(OH2)Cl]Cl (1) (H2L = pyridoxal thiosemicarbazone) are reported. The compound crystallizes in space group P2(1)/n, a = 12.128(2), b = 9.096(2), c = 13.592(2) A, beta = 108.65(2) degrees, U = 1420.7 A3, and Z = 4. The molecular structure consists of discrete cations [Cu(H2L)(OH2)Cl]+ and Cl- anions. Each copper atom is in an approximately square pyramidal environment involving the phenolic oxygen, the imine nitrogen, the sulphur, and a water oxygen in the equatorial positions, while a chlorine atom occupies the axial position. The structure of this complex is compared to that of the dimeric [(Cu(HL)(OH2))2]Cl2.2H2O (2) obtained under different experimental conditions, to that of a Co(III) complex with the same ligand [Co(HL)L].4.5H2O (3) and to that of the free ligand H2L, especially in relation to its biological activity. Compounds 1 and 2 have not antiviral action in vitro with respect to RNA viruses, show an inductive effect on Friend erythroleukemia cells (FLC), erythroid differentiation and a suppressive effect regarding FLC proliferation. Complex 3 and the free ligand do not have biological activity.

Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with antiproliferative activity.

Thiosemicarbazones are versatile organic compounds that present considerable pharmaceutical interest because of a wide range of properties. In our laboratory we synthesised some new metal-complexes with thiosemicarbazones derived from natural aldehydes which showed peculiar biological activities. In particular, a nickel complex [Ni(S-tcitr)(2)] (S-tcitr=S-citronellalthiosemicarbazonate) was observed to induce an antiproliferative effect on U937, a human histiocytic lymphoma cell line, at low concentrations (IC(50)=14.4microM). Therefore, we decided to study the interactions of this molecule with various cellular components and to characterise the induced apoptotic pathway. Results showed that [Ni(S-tcitr)(2)] causes programmed cell death via down-regulation of Bcl-2, alteration of mitochondrial membrane potential and caspase-3 activity, regardless of p53 function. The metal complex is not active on G(0) cells (i.e. fresh leukocytes) but is able to induce perturbation of the cell cycle on stimulated lymphocytes and U937 cells, in which a G(2)/M block was detected. It reaches the nucleus where it induces, at low concentrations (2.5-5.0microM), DNA damage, which could be partially ascribed to oxidative stress. [Ni(S-tcitr)(2)] is moreover able to strongly reduce the telomerase activity. Although the biological target of this metal complex is still unknown, the reported data suggest that [Ni(S-tcitr)(2)] could be a good model for the synthesis of new metal thiosemicarbazones with specific biological activity.

Synthesis, characterization and biological activity of two new polymeric copper(II) complexes with α-ketoglutaric acid thiosemicarbazone

In this paper we describe the synthesis of new copper complexes with alpha-ketoglutaric acid thiosemicarbazone. The crystal structures of the two compounds: [Cu(H(2)ct)Cl](n) [(Cu(H(2)ct)Cl)(2)] (1) and [Cu(Hct)](n).3nH(2)O (2) (H(3)ct=alpha-ketoglutaric acid thiosemicarbazone) have been determined by X-ray and spectroscopic methods. In 1 two independent copper atoms are present. Cu(1), in a nitrogen- and oxygen-bridged polymer, is a six-coordinated (4+2), Cu(2), five coordinated (4+1), is a chlorine-bridged dimer. In 2 the copper atom presents a penta-coordination, polymeric chains form layers and the -CH(2)CH(2)COO(-) groups bridge copper atoms. In 1 a monodentate and in 2 a syn-anti bidentate bridging carboxylate are present. The biological properties of 1 and 2 and also of the free ligand (H(3)ct) were tested in vitro and compared on Friend erythroleukemia cells (FLC) and on human leukemia cell lines K562 and U937. On the FLC cells the free ligand does not inhibit cell growth, but increases the DNA synthesis; complex 1 inhibits cell proliferation and increases the DNA synthesis; complex 2 inhibits cell growth, but induces a decrement of DNA synthesis and increases the reverse transcriptase activity. Regarding the human cell lines, both complexes show proliferation inhibition through an apoptosis mechanism on cell line U937, while they have no effects on the K562 line.

Synthesis, structural characterization and biological activity of p-fluorobenzaldehyde thiosemicarbazones and of a nickel complex.

New thiosemicarbazones (1-7), derived from p-fluorobenzaldehyde and differently substituted thiosemicarbazides, were synthetized and characterized by means of NMR and IR techniques. The p-fluorobenzaldehyde thiosemicarbazone Hfbt (1), the p-fluorobenzaldehyde 4-phenylthiosemicarbazone Ph-Hfbt (4) and complex [Ni(fbt)2] (8) were also characterized by X-ray diffractometry. Molecules 1 and 4 consist of two units: the p-fluorobenzaldehyde residue and the thiosemicarbazonic chain. In the reaction of 1 with NiAc2.4H2O, complex 8 was afforded. The molecular structure of 8 consists of the neutral molecules [Ni(fbt)2] with the metal placed on a symmetry centre. The coordination results in a square planar configuration and involves the sulphur atom and the hydrazine nitrogen atom of the two ligands in a trans configuration. Moreover, for compounds 1, 2, 4, and 8, assays of proliferation inhibition and apoptosis tests in vitro on human leukemia cell line U937 were carried out.

New methyl pyruvate thiosemicarbazones and their copper and zinc complexes: synthesis, characterization, X-ray structures and biological activity

By reacting thiosemicarbazides substituted on the aminic nitrogen with both alkyl or aryl groups, and methyl pyruvate a new group of methylpyruvate thiosemicarbazones (Hmpt) derivatives was obtained. These ligands were then treated with copper and zinc inorganic salts. All isolated compounds were characterized using spectroscopic methods. The single crystal structural analysis of the ligands Me-Hmpt x 0.5H2O 1, Et-Hmpt x H2O 2, Ph-Hmpt 5, Meph-Hmpt 6 showed that only compound 6 presents significant deviation from planarity. The X-ray structure of [Zn(Me-Hmpt)Cl2] x H2O 8 showed that in this complex Me-Hmpt behaves as a neutral ligand SNO terdentate and that the penta coordination is achieved by chloride ions according to spectroscopic and elemental analyses. On the basis of the analytical data the same behavior is proposed for the other zinc complexes. All the ligands in copper complexes seem to be monodeprotonated; nevertheless the same SNO behavior is expected. Tests on cell proliferation of human leukemic cell line U937 showed that the copper complex Cu(Et-mpt)Cl x H2O is the most active compound among those reported even though it is not able to induce apoptosis.

Synthesis, spectroscopic and structural characterization of chlorobis(methyl pyruvate thiosemicarbazone)copper(I) and chlorobis(triphenylphosphine) (methyl pyruvate thiosemicarbazone)copper(I) toluene solvate (2/1)

Abstract Two new compounds, chlorobis(methyl pyruvate thiosemicarbazone)copper(I), [Cu(Hmpt)2Cl] (A), and chlorobis(triphenylphosphine)(methyl pyruvate thiosemicarbazone)copper(I) toluene solvate (2/1), [Cu(PPh3)2(Hmpt)Cl]·0.5C7H8 (B) have been synthesized and characterized using spectroscopic studies and single-crystal X-ray diffraction methods at 293 K. Compound A crystallizes in space group C2/c, with a = 14.695(1), b = 13.775(1), c = 10.251(1) A, β = 113.38(1)°, V= 1904.7 A3; compound B crystallizes in space group P 1 , with a=17.871(7), b=10.681(2), c=11.695(7) A, α=74.90(1), β=86.65(4), γ=83.66(2)°, V=2141 A3. The crystal structures were solved by the heavy-atom method for A and by direct methods for B and refined to R values of 0.053 for both compounds. In A the copper and chlorine atoms lie on a crystallographic two-fold axis and the trigonal coordination around copper involves, besides chlorine, two sulfur atoms from two Hmpt molecules. In B the copper is tetrahedrally four-coordinated involving a chlorine atom, a sulfur atom from the Hmpt molecule and the phosphorus atoms of the two PPh3 molecules. In both compounds the ligand is neutral, monodentate through the sulfur atom and shows the configuration Z E Z about the C(2)N(3), C(1)N(2) and C(2)C(3) bonds (with respect to possible donating centres O(1), N(3) and S). The main vibrational bands are also reported and discussed.

SYNTHESIS, CHARACTERISATION AND BIOLOGICAL ACTIVITY OF THREE COPPER(II) COMPLEXES WITH A MODIFIED NITROGENOUS BASE : 5-FORMYLURACIL THIOSEMICARBAZONE

Three Cu(II) co-ordination compounds with a novel ligand, 5-formyluracil thiosemicarbazone (H3ut), have been synthesised and characterised by single-crystal X-ray diffraction and subsequently tested in vitro on human leukemic cells. The crystal structures revealed, in all three cases, a square pyramidal co-ordination geometry of the copper atom with the ligand lying on the basal plane and behaving as an SNO terdentate ligand. These three compounds have been tested on human leukemic cell line K562 and CEM. In these experiments the complexes have demonstrated to inhibit cell growth and one of them to induce apoptosis. In the paper we also report the spectrophotometric characterization of the free ligand.

Transition-metal complexes of isatin-β-thiosemicarbazone. X-ray crystal structure of two nickel complexes

Manganese, iron, cobalt, nickel, copper and zinc complexes of isatin-beta-thiosemicarbazone (H2L) have been synthesized and spectroscopically characterized The X-ray crystal structures of two nickel complexes, namely [Ni(HL)2]. EtOH (1) and [Ni(HL)2]. 2DMF (2), reveal a distorted octahedral coordination with the monodeprotonated ligand that behaves as an O,N,S terdentate. Different packing interactions are determined by the presence of different crystallization solvents, i.e., ethanol in 1 and dimethylformamide (DMF) in 2. 1H and 13C NMR studies of the ligand and zinc complexes in solution were carried out and a complete assignment for the ligand was made by homodecoupling, gradient assisted 2D 1H-13C HMQC and HMBC NMR spectroscopy. Biological studies, carried out in vitro on human leukaemic cell lines U937, have shown that the free ligand and the copper (II) complex are more active in the inhibition of cell proliferation than the nickel complexes. No compound was able to induce apoptosis.