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Two Palladium complexes are presented as a promising alternative to platinum drugs disadvantages, controlling the speciation and limiting toxicity. Their interaction vs. biological targets and their efficiency are demonstrated, being more specific than the benchmark cisplatin drug.

Thiosemicarbazones (TSCNs) constitute a broad family of compounds (R1R2C=N-NH-C(S)- NR3R4), particularly attractive because many of them display some biological activity against a wide range of microorganisms and cancer cells. Their activity can be related to their electronic and structural properties, which offer a rich set of donor atoms for metal coordination and a high electronic delocalization providing different binding modes for biomolecules. Heterocycles such as pyrrole, imidazole and triazole are present in biological molecules such as Vitamine B12 and amino acids and could potentially target multiple biological processes. Considering this, we have explored the chemistry and biological properties of thiosemicarbazones series and their complexes bearing heterocycles such as pyrrole, imidazole, thiazole and triazole. We focus at the chemistry and cytotoxicity of those derivatives to find out the structure activity relationships, and particularly we analyzed those examples with the TSCN units in which the mechanism of action information has been profoundly studied and pathways determined, to promote future studies for heterocycle derivatives.

Three thiosemicarbazone derivatives, namely 4-(dimethylamino)benzaldehyde 4,4-dimethylthiosemicarbazone (HL1), 4-(dimethylamino)benzaldehyde thiosemicarbazone (HL2), and 4-(dimethylamino)benzaldehy...

The synthesis and characterization of three new platinum complexes, with 3,5-diacetyl-1,2,4-triazole bis(4-N-isopropylthiosemicarbazone) as a ligand, are reported. The specific conditions under which solvent coordination takes place are reported and the X-ray structure of the complex with one solvent molecule of dimethyl sulfoxide is resolved. Analysis of the reactivity of these platinum compounds aids in finding the best solution profile for biological investigations. Then, the interactions of the complexes with biological models, such as calf-thymus DNA, are studied by using UV spectroscopy and tracking the changes in electrophoretic mobility produced in the supercoiled plasmid DNA model. Initial screening of these potential antitumoral compounds indicates possible selective antitumoral action.

Novel bisphosphonate platinum complexes: [Pt(isopropylamine) 2 (BP)]NO 3 (BP = pamidronate and alendronate) have been synthesized and characterized. Their monomeric structure contains a bisphosphonate acting as chelate ligand through its oxygen atom donors, conferring the compound's cationic structure with a good solubility in water. The study of the compounds in solution showed high stability up to 24 h. The cytotoxicity in cancer cell lines has been assessed. We also present preliminary studies on the evaluation of the affinity towards biological targets such as DNA (both calf thymus DNA and supercoiled plasmid DNA) and hydroxyapatite where the complexes showed a low DNA interaction, but a clear affinity for hydroxyapatite comparing to their precursors.

We describe the direct coupling of alcohols and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivatives. Using this approach, a family of trans-Pt(II) compounds with amine ligands bearing long perfluorinated chains was prepared, as these chains potentially endow the complexes with thermoactivatable properties. Related compounds with alkyl chains in place of the perfluorinated chains were also prepared as controls using the same direct coupling method. The stability of the complexes in solution, their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 °C and following exposure to elevated temperatures (that mimic the temperatures employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents.

Preparation and characterization of a new 4N-p-chlorophenyl substituted thiosemicarbazone ligand, H3L2, and its derived palladium(II) and platinum(II) complexes, [Pt(HL2)(PPh3)] and [Pd(HL2)(PPh3)], is described. The molecular structures of the two new metal complexes have been determined by single crystal X-ray diffraction. In both complexes the metal ion is four-coordinated with a [N2SP] donor environment, via one triazole nitrogen atom, the azomethine nitrogen and thione sulfur atoms of the thiosemicarbazone moiety and a phosphorous atom from the triphenylphosphine coligand. The biological activity of the new compounds synthesized was initially explored by determining their antiproliferative activity in vitro against T-47D, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumor properties, especially H3L2 since is capable not only to circumvent cisplatin resistance in A2780cisR cells but also to exhibit high antiproliferative activity in breast cancer T-47D cells.

Preparation and characterization of 3,5-diacetyl-1,2,4-triazol mono(4-phenylthiosemicarbazone) ligand, H3L, and its derived palladium(II) and platinum(II) complexes, [Pd(HL)(PPh3)] and [Pt(HL)(PPh3)], is described. The molecular structures of the two new metal complexes have been determined by single crystal X-ray diffraction. In both complexes the metal ion is four-coordinated with a [N2SP] donor environment, via one triazole nitrogen atom, the azomethine nitrogen and thione sulfur atoms of the thiosemicarbazone moiety and a phosphorous atom from the triphenylphosphine coligand. The cytotoxicity of the new compounds synthesized was investigated in vitro against T-47D, A2780 and A2780cisR human cancer cell lines, being H3L the species with the highest activity. In addition, the DNA binding ability of H3L with calf thymus DNA was explored by UV–Vis absorption spectroscopy.

Upon reaction with RuCl2(PPh3)3 in toluene in presence of triethylamine, 2,6-diacetylpyridine mono(4-methoxyphenyl thiosemicarbazone) undergoes an unusual and interesting chemical transformation leading to the formation of a dithiobiurea ruthenium(II) complex. The new complex was characterized by analytical, spectroscopic and single crystal X-ray diffraction techniques. The crystallographic study confirmed the presence of 1,6-(4-metoxyphenyl)-2,5-dithiobiurea acting as monoanionic SNS tridentate ligand. Thus the coordination geometry around the ruthenium(II) ion is a distorted octahedral where the SNS donor set of the ligand and one co-ordinated chlorido constitute the equatorial plane. The remaining apical coordination positions are filled up by two triphenylphosphines.

Two Pd(II) and Pt(II) complexes with two pyrrol-2-carbaldehyde N-p-chlorophenylthiosemicarbazone ligands are designed and characterized showing mononuclear structures. An important pharmacological property for both compounds is the high selectivity for tumor cells and a lack of activity in healthy cells. The Pd(II) compound shows a higher antitumor activity and selectivity than the Pt(II) compound. Both complexes present a variety of biological interactions: with DNA models (pBR322 and CT DNA), proteins (lysozyme and RNase) and other biological targets like proteosome. Our results show that the Pd(II) complex is a more interesting candidate for potential anticancer therapies than the Pt(II) complex, and we provide new insight into the design and synthesis of palladium compounds as potential antitumor agents., Puede accederse a los datos primarios de este trabajo haciendo clic en "Documentos relacionados"., Facultad de Ciencias Exactas, Centro de Química Inorgánica

One mononuclear and another dinuclear Pd(II) complexes bearing a α-N-heterocyclic thiosemicarbazone ligand have been synthesized, fully characterized and studied as biological agents. In both complexes, the palladium center is coordinated to 3,5-diacetyl-1,2,4-triazol bis(N4,N4-dimethylthiosemicarbazone) via three sites (N, N and S). Their binding ability to DNA has been evaluated using spectroscopic and biophysical techniques. Molecular docking and molecular dynamics calculations supports the existence of a minor groove binding mode between the studied compounds and DNA.

Preparation and characterization of a novel 2,6-diacetylpyridine mono(4-methoxyphenyl-thiosemicarbazone), H2L, is described. Treatment of H2L with PdCl2(PPh3)2 gave the neutral mononuclear complex [PdL(PPh3)]. Both compounds have been characterized by elemental analysis and FAB+ spectrometry and by IR and 1H NMR spectroscopy. Recrystallization of [PdL(PPh3)] in DMSO led to the isolation of two solvatomorphic forms of this compound which were studied by X-ray crystallography. In each solvatomorph, the thiosemicarbazone ligand acts as dianionic [CNS] tridentate donor coordinating to the palladium(II) ion in a square planar geometry through the iminic nitrogen atom, the sulfur atom and one ortho carbon atom of the pyridine ring and the fourth site is occupied by P atom from the PPh3 coligand. The overall molecular conformation of the two solvatomorphs is very similar and the largest difference lies in the orientation of the methyl group of the 4-methoxyphenyl substituent with respect to the sulfur atom.

The authors research work presented in this review was supported by Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III (PI040354 and PI080525), Comunidad de Madrid (GR/SAL/0180/2004) and Universidad Autonoma de Madrid-Comunidad de Madrid (CCG08-UAM/SAL-4000) of Spain

This is the peer reviewed version of the following article: European Journal of Inorganic Chemistry 34 (2007): 5433-5438, which has been published in final form at http://dx.doi.org/10.1002/ejic.200700619. This article may be used for non-commercial purposes in accordance With Wiley-VCH Terms and Conditions for self-archiving, The new cyclic 5-ethoxy-4-ethyl-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]- triazine-3-thione ligand (HTa3T-Et) has been obtained by an intramolecular cyclization reaction of α-diphenylethanedione bis(4- ethylthiosemicarbazone) (H2BbTSC-Et). The cyclization may be promoted either by hydroxylic solvents or by ZnII ions. Thus, the reaction of H2BbTSC-Et with ZnCl2 led to the formation of [Zn(HTa3T-Et)2Cl2] containing not the ligand H 2BbTSC-Et but the cyclic HTa3T-Et ligand that forms during the reaction. On the other hand, crystallization of H2BbTSC-Et from DMSO/EtOH produces a cocrystal containing the open-chain H2BbTSC-Et ligand together with the cyclic HTa3T-Et molecules, which are linked to a DMSO molecule by hydrogen bonds. However, reaction of the cocrystal with Pd II ions yields a planar tetracoordinate complex in which only the H2BbTSC-Et ligand, in the deprotonated form, is present. The preparation and molecular structures of these compounds are discussed, We are grateful to Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (PI040354) of Spain for financial support

The reaction of zinc bromide with the pentadentate chelating ligand 2, 6-diacetylpyridine bis(thiosemicarbazone) (H2L1) yields the formation of a novel complex. Recrystallization in a acetone/water solution leads us to isolate the mixed ligand complex of [Zn(H2L1)Br0.49(OH)0.51]2·(HSO4)2·6H2O, structurally characterized. The complex is a dimer in which each zinc atom is seven-co-ordinated with the SNNNS-chelating ligand occupying the five equatorial positions, a bromine atom or hydroxo group in one of the two axial positions and a sulfur atom of the centrosymmetrical molecule occupies the other axial site making a bridge between the two zinc atoms. To the best of our knowledge is the first S-bridged dimeric Zinc(II) complex derived from 2, 6-diacetylpyridine bis(thiosemicarbazone) ligand. The MALDI-TOF mass, solid state IR and 1H NMR (in DMSO solution) spectra are also discussed.

A new bis(thiosemicarbazone) ligand, H 5 L 1 , derived from 3,5-diacyl-1,2,4-triazole and 4-phenylthiosemicarbazide has been prepared. Treatment of this ligand with Li 2 [PdCl 4 ] produced the binuclear palladium(II) compound, [Pd 2 (μ-H 3 L 1 ) 2 ]. The compounds were characterized by elemental analyses (C, H, N, S), mass spectrometry, IR, UV–Vis and 1 H NMR spectroscopy and electrochemical techniques. The crystal and molecular structure of [Pd 2 (μ-H 3 L 1 ) 2 ] · 4DMSO · H 2 O with dideprotonation of triazolic and thiosemicarbazone NH groups has been determined by single X-ray diffraction. The H 5 L 1 ligand coordinates, in a dideprotonated form, to the palladium ions in a new tridentate fashion (SNN) and S-bridging bonding modes. Thus, the molecular units of the palladium complex are stacked as dimers.

The following article appeared in Inorganic Chemistry Frontiers 2 (2015): 75-84 and may be found at http://dx.doi.org/10.1039/C4QI00128A, reproduced by permission of The Royal Society of Chemistry, Preparation and characterization of the new ligand 3,5-diacetyl-1,2,4-triazol bis(4N-p -chlorophenylthiosemicarbazone), H5L1, and its bimetallic complexes [Pd(µ-H3L1)]2 and [Pt(µ-H3L1)]2, is described. The molecular structure of the complexes, determined by single crystal X-ray crystallography, reveals that each ligand coordinates, in an asymmetric dideprotonate form, to the metal ions in a square planar geometry. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, T-47D, A2780 and A2780cis R human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumor properties, especially H5L1 since exhibit excellent antiproliferative activity surpassing the activity of cisplatin against three of the four tumor cell lines studied. The DNA binding ability of H5L1 and [Pt(µ-H3L1)]2 with calf thymus DNA in Tris-HCl buffer solution (pH=7.2) was explored by UV-Vis absorption spectroscopy and viscosity measurements. These data indicated that both compounds bind to DNA by a groove binding mode, We are grateful to Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (PI1100659), of Spain for financial support

We have prepared mono- and binuclear complexes of Zn(II) and Cd(II) with bis(2-pyridyl aldehyde) thiocarbodiazone (H(2)L(1)) and bis(methyl 3-pyridyl ketone) thiocarbodiazone (H(2)L(2)). Cytotoxicity data against the ovarian tumor cell line A2780cisR (acquired resistance to cisplatin) indicate that the mononuclear complex Cd/H(2)L(2) (1) and the binuclear complex Cd(2)/H(2)L(1) (4) are able to circumvent cisplatin resistance and that their cytotoxic activity does not substantially vary after depletion of intracellular levels of glutathione. Moreover, DNA binding studies show that complexes 1 and 4 have higher efficiency than cisplatin at forming DNA interstrand cross-links in both naked pBR322 plasmid and A2780cisR cellular DNA. Interestingly, the thiocarbodiazone ligands alone do not show the biological properties of complexes 1 and 4. Altogether these results suggest that DNA interstrand cross-link formation by compounds 1 and 4 might be related with their cytotoxic activity in cisplatin-resistant cells. We think that compounds 1 and 4 may represent a novel structural lead for the development of cadmium cytotoxic agents capable of improving antitumor activity in cisplatin-resistant tumors.

It is known that metallic complexes of methyl 2-pyridyl ketone thiosemicarbazone (HL1) and p-isopropyl benzaldehyde thiosemicarbazone (HL2) may have potential antitumor activity. We have prepared complexes of HL1 and HL2 with Zn(II) and Cd(II). The cytotoxic activity shown by these compounds against cell lines sensitive and resistant to cis-diamminedichloroplatinum(II) (cis-DDP) indicates that coupling of HL1 and HL2 to Zn(II) and Cd(II) centers may result in metallic complexes with important biological properties since they display IC50 values in a microM range similar to that of the antitumor drug cis-DDP. Moreover, it is interesting to note that the Zn/HL2 complex exhibits specific cytotoxic activity against Pam-ras cells (cis-DDP resistant cells which over-express the H-ras oncogene) with an in vitro therapeutic index of 3.26 versus 0.78 for cis-DDP. Treatment of Pam-ras cells with the IC50 value of the Zn/HL2 compound induces a 'DNA ladder' (fragmentation of genomic DNA in nucleosome units) indicative of apoptosis in this ras-transformed cell line. In contrast, a 'DNA smear' (non-specific fragmentation of genomic DNA) is observed in Pam 212 normal cells treated with the IC50 of this compound. The analysis by circular dichroism (CD) spectroscopy of the interaction of the Zn/HL2 compound with calf thymus DNA (CT DNA) indicates that it produces stronger alterations on the double helix conformation than cis-DDP. So, these results suggest that Zn/HL2 may be considered a potential antitumor agent.

The complex [Ni(HL1)2]Cl2, 1, (HL1 = methyl(2-pyridyl)ketone thiosemicarbazone) has been prepared by reaction of HL1 with nickel(II) chloride and the complex [Ni(L1)NCS], 2, has been prepared by transmetallation of [Pb2(HL1)(L1)(NCS)3] with an excess of nickel(II) chloride. The new complexes have been characterized by spectroscopic techniques and the crystal and molecular structure of [Ni(L1)NCS] has been determined. The nickel atom has square-planar geometry with three donor atoms (NNS) belonging to L1; the fourth coordination site is occupied by an isothiocyanate ion. This results in a planar tricyclic ligating system containing one heterocyclic and two five-membered chelate rings.

NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Inorganic Biochemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Inorganic Biochemistry 138 (2014): 16-23 DOI http://dx.doi.org/10.1016/j.jinorgbio.2014.04.017, Preparation and characterization of 2,6-diacetylpyridine bis(4N-p-chlorophenylthiosemicarbazone) ligand, H2L, and its palladium(II) and platinum(II) complexes [PdL] and [PtL], is described. The molecular structure of the two new complexes has been determined by single crystal X-ray diffraction. The ligand acts as dianionic tetradentate donor coordinating to the metal center in a square planar geometry through the pyridine nitrogen atom and the azomethine nitrogen and thione sulfur atoms from one thiosemicarbazone arm, the fourth coordination position is occupied by the hydrazine nitrogen atom of the other arm. New free ligand and its metal complexes have been evaluated for antiproliferative activity in vitro against NCI-H460, T-47D, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumor properties, especially H2L and [PtL] since they are capable of not only circumvent cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in breast cancer T-47D cells. The interaction of H2L with calf thymus DNA was also investigated and its binding constant (Kb) determined, We are grateful to Ministerio de Economía y Competitividad, Instituto de Salud Carlos III of Spain (PI1100659) for financial support

A new organometallic compound containing a heterocyclic amine linked to the ferrocenoyl moiety was synthesized and characterized by elemental analysis (C, H, N), mass spectrometry, IR and 1HNMR spectroscopy. Its crystal and molecular structure was determined by X-ray diffraction methods. This compound crystallizes in the monoclinic P21 space group, a = 5.80260(10), b = 9.24160(10), c = 12.3510(2) A, β = 92.8200(10)° and Z = 2. An interesting feature of the crystal structure is the presence of an intermolecular non-classical hydrogen bonding interaction between a cyclopentadienyl hydrogen atom and a carbonyl oxygen group. The electrochemical behaviour of this compound is characterized by the reversible one-electron oxidation of the ferrocene moiety.

NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Inorganic Biochemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in JOURNAL OF INORGANIC BIOCHEMISTRY 125 (2013): 26-31 DOI http://dx.doi.org/10.1016/j.jinorgbio.2013.04.005, Preparation and characterization of four novel 2,6-diacetylpyridine bis(4N-tolylthiosemicarbazonato) palladium(II) and platinum(II) complexes, [PdL1-2] and [PtL1-2], are described. All compounds have been characterized by elemental analysis and by IR and NMR spectroscopy, and the crystal and molecular structures of complexes [PdL 2] and [PtL2] have been determined by a single crystal X-ray diffraction. The ligands act as dianionic tetradentate donors coordinating to the metal center in a square planar geometry through the N pyridinic atom and the Niminic and the S atoms from one thiosemicarbazone arm, the fourth coordination position is occupied by the Nhydrazinic of the other arm. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, HepG2, MCF-7, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that [PdL1], [PdL2] and [PtL2] may be endowed with important antitumor properties since they are capable of not only circumventing cisplatin resistance in A2780cisR cells but also exhibiting high antiproliferative activity in breast cancer MCF-7 cells. Subsequent toxicity study, in LLC-PK1 cells, has also been carried out and shows that none of these compounds are in vitro toxic in the tested concentration range, We are grateful to Ministerio de Economía y Competitividad, Instituto de Salud Carlos III of Spain (PI080525 and PI1100659) for financial support

NOTICE: this is the author’s version of a work that was accepted for publication in Inorganic Chemistry Communications. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Inorganic Chemistry Communications 27 (2013): 5-8 DOI http://dx.doi.org/10.1016/j.inoche.2012.10.022, Reaction of 2,6-diacetylpyridine bis(4N-o- tolylthiosemicarbazone), H2L1, with K2PtCl 4 and further recrystallization in DMSO/MeOH of the [PtL1] complex obtained, led to the isolation of the novel platinum complex, [PtL 2], which was structurally characterized by single crystal X-ray diffraction. The molecular structure shows that the ligand has undergone an unexpected chemical transformation viz. reduction of one of the terminal phenyl rings into cyclohexyl. The resulted asymmetrical ligand acts a dianionic tetradentate donor, coordinating to the platinum (II) center in a square planar geometry through the Npyridinic atom and the Niminic and the S atoms from one thiosemicarbazone arm, the fourth coordination position is occupied by the Nhydrazinic atom of the other arm, We are grateful to Ministerio de Economía y Competitividad. Instituto de Salud Carlos III of Spain (PI080525 and PI1100659) for financial support

A new polidentate ligand, 3,5-diacyl-1,2,4-triazolebis(4-methylthiosemicarbazone), (H5L) has been synthesised; complexation of this ligand with Li2PdCl4 leads to a novel stable [Pd2(μ-H3L)2] macrocyclic cage which was characterised by X-ray crystallography. The ligand coordinates to the Pd atoms in a new tridentate fashion, forming a chelating and a bridging bonding modes.

this is the author’s version of a work that was accepted for publication in Journal of Inorganic Biochemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Inorganic Biochemistry 105.12 (2011): 1613-1622 DOI http://dx.doi.org/10.1016/j.jinorgbio.2011.08.014, Treatment of 4N-monosubstituted bis(thiosemicarbazone) ligands of 3,5-diacetyl-1,2,4-triazol series with lithium tetrachloridopalladate gave the dinuclear complexes of general formula [Pd(μ-H 3L 1-5)] 2, but using dichloridobistriphenylphosphinepalladium(II) salt, the first mononuclear bis(thiosemicarbazone)-palladium-triphenylphosphine complexes of the 3,5-diacetyl-1,2,4-triazol series, [Pd(H 3L 1-5)PPh 3], have been obtained. All the compounds have been characterized by elemental analysis and by IR and NMR spectroscopy, and the crystal and molecular structures of dinuclear complexes [Pd(μ-H 3L 3)] 2 and [Pd(μ-H 3L 5)] 2 as well as mononuclear complexes [Pd(H 3L 1)PPh 3], [Pd(H 3L 2)PPh 3], [Pd(H 3L 3)PPh 3] and [Pd(H 3L 4)PPh 3] have been determined by X-ray crystallography. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, A2780 and A2780cisR human cancer cell lines. Subsequent toxicity study, on normal renal LLC-PK1 cells, shows that all compounds investigated exhibit very low toxicity on kidney cells with respect to cisplatin, We are grateful to Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (PI080525), Universidad Autónoma de Madrid and Comunidad de Madrid (CCG08-UAM/SAL-4000) of Spain for financial support

Dalton Transactions 40.21 (2011): 5738-5745. Reproduced by permission of The Royal Society of Chemistry, The preparation and characterization of three novel 4N- monosubstituted bis(thiosemicarbazone) ligands of 3,5-diacetyl-1,2,4-triazol series and their dinuclear platinum complexes are described. The crystal and molecular structure of the [Pt(μ-H3L3)]2 complex derived of 3,5-diacetyl-1,2,4-triazol bis(4N-p- tolylthiosemicarbazone), H5L3, has been resolved by single crystal X-ray diffraction. The ligands coordinate, in an asymmetric dideprotonate form, to the platinum ions in a tridentate fashion (NNS) and S-bridging bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumour properties since are capable of not only circumventing cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in human non-small cell lung cancer NCI-H460 cells. The interactions of these compounds with calf thymus DNA was investigated by UV-vis absorption and a nephrotoxic study, in LLC-PK1 cells, has also been carried out, We are grateful to Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (PI080525), Universidad Autónoma de Madrid and Comunidad de Madrid (CCG08-UAM/SAL-4000) of Spain for financial support

Dalton Transactions 39.30 (2010): 7059-7065. Reproduced by permission of The Royal Society of Chemistry, The preparation and characterization of 3,5-diacetyl-1,2,4-triazol bis(4,4-dimethylthiosemicarbazone) ligand, H3L1, and its dinuclear platinum complex [Pt(μ-HL1)]2 is described. The crystal and molecular structure of the platinum complex has been resolved by single crystal X-ray diffraction. The ligands coordinate, in an asymmetric dideprotonate form, to the platinum ions in a tridentate fashion (NNS) and S-bridging bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The new compounds synthesized together with the analogous monosubstituted ligand 3,5-diacetyl-1,2,4-triazol bis(4-methylthiosemicarbazone) (H5L2) and its dinuclear platinum(ii) complex [Pt(μ-H3L2)]2 have been evaluated for antiproliferative activity in vitro against NCI-H460, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumor properties, especially H3L 1 and [Pt(μ-H3L2)]2 since they not only circumvent cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in human non-small cell lung cancer NCI-H460 cells. Subsequent nephrotoxic study, in LLC-PK1 cells, show that the four compounds investigated exhibit very low nephrotoxicity with respect to cisplatin, We are grateful toMinisterio de Ciencia e Innovación, Instituto de Salud Carlos III (PI080525), Universidad Autónoma de Madrid and Comunidad de Madrid (CCG08-UAM/SAL-4000) of Spain for financial support. C. J. also thanks Erasmus Programme for its Research Placement at Universidad Autónoma de Madrid

alpha-N-Heterocyclic thiosemicarbazones, (N)-TSCs, are potent inhibitors of ribonucleotide reductase (RR). This enzyme plays a critical role in DNA synthesis and repair, and is a well-recognized target for cancer chemotherapeutic agents. In this review the structural features of (N)-TSCs, required for maximum antitumour activity have been explored. Special attention is given to the mechanisms of action and structure-activity relationships.

The preparation of new palladium(II) and platinum(II) complexes derived from α-diphenyl ethanedione bis(thiosemicarbazone), 1 , and α-diphenyl ethanedione bis(4-ethylthiosemicarbazone), 2 , is described. The palladium complexes 3 and 4 and platinum complexes 5 and 6 have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB + ) and spectroscopic studies (IR, 1 HNMR). The crystal and molecular structures of the dimeric cyclopalladated compound 4 and the mononuclear platinum complex 6 have been determined by single crystal X-ray diffraction. The cytotoxic activity of the free ligands and palladium and platinum complexes against human A2780 and A2780 cis R (acquired resistance to cisplatin) epithelial ovarian carcinoma cells lines is also reported. The IC 50 values for compounds 1 , 5 and 6 were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar. Furthermore, the compounds largely retain their activity in the A2780 cis R cell line, having a much better resistance factor than cisplatin in the pair of cell lines tested.

NOTICE: this is the author’s version of a work that was accepted for publication in Inorganic Chemistry Communications. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Inorganic Chemistry Communications 10.1 (2007): 97-100 DOI http://dx.doi.org/10.1016/j.inoche.2006.09.016, A novel tetranuclear [Pd4(μ2-η2-S2)(H2L1)2] complex, where H2L1 is the anion of 3,5-diacetyl-1,2,4-triazole bis(4-ethylthiosemicarbazone), was synthesized and structurally characterized by single crystal X-ray diffraction. The molecular structure shows an unexpected μ2-η2-S2 bridge, which is shared by all the four palladium atoms. Each trideprotonate 3,5-diacetyl-1,2,4-triazole bis(4-ethylthiosemicarbazone) ligand acts as a hexadentate in a symmetrical manner bridging two metal ions through the two adjacent nitrogen atoms of the central triazole ring. The molecular packing is characterized by hydrogen bond interactions to form a 3D supramolecular architecture with channels running down the c* axis in which the lattice water molecules are encapsulated, We are grateful to Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (PI040354) and Comunidad Autónoma de Madrid (GR/SAL/0180/2004) of Spain for financial support

The preparation of platinum(II) complexes derived from 3,5-diacetyl-1,2,4-triazol bis(4-phenylthiosemicarbazone) (H(5)L(1)), 3,5-diacetyl-1,2,4-triazol bis(thiosemicarbazone) (H(7)L(2)), 3,5-diacetyl-1,2,4-triazol bis(4-methylthiosemicarbazone) (H(5)L(3)) and 3,5-diacetyl-1,2,4-triazol bis(4-ethylthiosemicarbazone) (H(5)L(3)) is described. The new complexes [Pt(mu-H(3)L(1))](2), [Pt(mu-H(5)L(2))](2), [Pt(mu-H(3)L(3))](2) and [Pt(mu-H(3)L(4))](2) have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB(+)) and spectroscopic studies. The crystal and molecular structure of compounds [Pt(mu-H(3)L(1))](2), parent ligand H(5)L(1) and [Pt(mu-H(3)L(3))](2) have been determined by single crystal X-ray diffraction. The ligands coordinate, in a dideprotonate form to the platinum ions in a new tridentate fashion (NNS) and S-brigding bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The testing of the cytotoxic activity of the synthesized compounds together with their palladium analogues against human A2780 and A2780cisR epithelial ovarian carcinoma cells lines suggests that the compounds may be endowed with important antitumor properties since they show IC(50) values in a micromolar range similar to those of cisplatin. The structure and antitumor activity relationships of platinum and palladium complexes are also discussed.

The complexes [M(HL)L]ClO4(HL = methyl 2-pyridyl ketone thiosemicarbazone; M = Cu 1 or Co 2) have been prepared from the reaction of HL with the appropriate perchlorate salt; [Cu(HL)L]NCS 3 was also prepared by transmetallation of [Pb2(HL)L(NCS)2]NCS with an excess of copper(II) perchlorate. The new complexes have been characterized by spectroscopic techniques and the crystal structure of 3 has been determined: green triclinic crystal, a= 10.150(2), b= 10.350(2), c= 11.890(2)A, α= 88.55(3), β= 83.28(3), γ= 63.26(3)°, space group P, Z= 2. The copper atom is six-co-ordinated by two NNS donor sets from terdentate ligands.

Here, we present data on the activity of benzyl bis(thiosemicarbazone); 3,5-diacyl-1,2,4-triazole bis(4-methylthiosemicarbazone) and their Pd(II) complexes against the replication of wild type and of acyclovir (ACV)-resistant, herpes simplex virus type 1 (HSV 1) and type 2 (HSV 2) strains. The data were compared to those under the action of acyclovir. The testing of cytotoxic activity suggests that these compounds may be endowed with important antiviral properties. It is interesting to note that the Pd(II)-benzyl bis(thiosemicarbazone) complex, 2, exhibits a significant activity against acyclovir-resistant viruses R-100 (HSV 1) and PU (HSV 2) with an in vitro selectivity index (SI) of 8.0 vs. 0.01 for acyclovir. This complex also negatively influenced the expression of key structural HSV 1 proteins (VP23, gH and gG/gD), thus suppressing simultaneously virus entry, transactivation of virus genome, capsid assembly, and cell-to-cell spread of infectious HSV progeny.

The preparation of palladium(II) complexes of 3,5-diacyl-1,2,4-triazole bis(thiosemicarbazone) (H 2 L 2 ), 2,6-diacylpyridine bis(thiosemicarbazone) (H 2 L 3 ) and benzyl bis(thiosemicarbazone) (H 2 L 4 ) is described. The new complexes [PdCl 2 (H 2 L 2 )] ( 1 ), [PdCl 2 (H 2 L 3 )] ( 2 ) and [PdL 4 ] · DMF ( 3 ) have been characterized by elemental analyses and spectroscopic studies (IR, 1 H NMR and UV–Vis). The crystal and molecular structure of PdL 4 · DMF (L=bideprotonated form of benzyl bis(thiosemicarbazone)) has been determined by single-crystal X-ray diffraction: green triclinic crystal, a =10.258(5), b =10.595(5), c =11.189(5) A, α =97.820(5), β =108.140(5), γ =105.283(5)°, space group P 1, Z =1. The palladium atom is tetracoordinated by four donor atoms (SNNS) from L 4 to form a planar tricyclic ligating system. The testing of the cytotoxic activity of compound 3 against several human, monkey and murine cell lines sensitive (HeLa, Vero and Pam 212) and resistant to cis -DDP (Pam- ras ) suggests that compound 3 might be endowed with important antitumor properties since it shows IC 50 values in a μM range similar to those of cis -DDP [ cis -diamminedichloroplatinum (II)]. Moreover, compound 3 displays notable cytotoxic activity in Pam- ras cells resistant to cis -DDP (IC 50 values of 78 μM versus 156 μM, respectively). On the other hand, the analysis of the interaction of this novel Pd-thiosemicarbazone compound with DNA secondary structure by means of circular dichroism spectroscopy indicates that it induces on the double helix conformational changes different from those induced by cis -DDP.

The syntheses of 3,4,10,11-tetraphenyl-1,2,5,6,8,9,12,13-octaazacyclotetradeca-7, 14-dione-2,4,9,11-tetraene (dbdch) and 6-methoxy-1,6-diphenyl-4-oxo-3,4,5,6-tetrahydro-2,3,5-triazine (bsc) and their complexes with divalent metal ions (copper, nickel, cobalt, zinc, cadmium and mercury) are reported. All compounds were characterized by 1H n.m.r., 13C n.m.r., i.r. and u.v.-vis. spectroscopy and by FAB mass spectrometry; possible structures are presented and discussed.

Dalton Transactions 41.40 (2012): 12538-12547. Reproduced by permission of The Royal Society of Chemistry, The preparation and characterization of the new 3,5-diacetyl-1,2,4-triazol bis(4-cyclohexyl thiosemicarbazone) ligand, H5L1, is described. Treatment of H5L1 with K2PtCl 4 gave the dinuclear complex [Pt(H3L1)] 2, 1, but using MCl2(PPh3)2 where M = Pd or Pt, mononuclear complexes 2 and 3, of general formula [M(H 3L1)PPh3], were obtained. Subsequent reaction of the [Pd(H3L1)PPh3] complex with PdCl 2(PPh3)2 yielded a new dinuclear complex [(PPh3)Pd(H2L1)PdCl], 4. All compounds have been characterized by elemental analysis and FAB+ spectrometry and by IR and NMR spectroscopy. The molecular structures of mononuclear complexes 2 and 3 and dinuclear complex 4 have been determined by X-ray crystallography. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, HepG2, MCF-7, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that the H5L1 ligand and [Pt(H3L1)]2, complex 1, may be endowed with important cytotoxic properties since they are capable of not only circumventing cisplatin resistance in A2780cisR but also exhibit antiproliferative activity in NCI-H460. The interactions of these compounds with calf thymus DNA were investigated by UV-vis absorption and a nephrotoxic study, in LLC-PK1 cells, has also been carried out, We are grateful to Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (PI080525 and PI1100659), of Spain for financial support