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Perchlorate ions induce structural diversity in a thiosemicarbazone copper(ii) system, whose aqueous chemistry includes desulfurization reactions even at physiological pH values.

Thiosemicarbazones and their metal derivatives have long been screened as antitumor agents, and their interactions with DNA have been analysed. Herein, we describe the synthesis and characterization of compounds containing [CuL]+ entities (HL = pyridine-2-carbaldehyde thiosemicarbazone) and adenine, cytosine or 9-methylguanine, and some of their corresponding nucleotides. For the first time, crystal structures of adenine- and 9-methylguanine-containing thiosemicarbazone complexes are reported. To the best of our knowledge, the first study on the affinity thiosemicarbazone–RNA is also provided here. Experimental and computational studies have shown that [CuL(OH2)]+ entities at low concentration intercalate into dsRNA poly(rA)·poly(rU) through strong hydrogen bonds involving uracil residues and π–π stacking interactions. In fact, noncovalent interactions are present both in the solid state and in solution. This behaviour diverges from that observed with DNA duplexes and creates an optimistic outlook in achieving selective binding to RNA for subsequent possible medical applications., Obra Social “la Caixa” (OSLC-2012-007), Ministerio de Economía y Competitividad and FEDER funds (CTQ2013-48937-C2-1-P, CTQ2015-70371- REDT, MAT2012-34740 and CTQ2014-58812-C2-2-R), Junta de Castilla y León (BU237U13), the Basque Government (IT-779- 13), Gerencia Regional de Salud, Consejería de Sanidad, Junta de Castilla y León (GRS 1023/A/14 and GR172).

Colorectal cancer is the third most common type of cancer and has a high incidence in developed countries. At present, specific treatments are being required to allow individualized therapy depending on the molecular alteration on which the drug may act. The aim of this project is to evaluate whether HPTSC and HPTSC* thiosemicarbazones (HPTSC = pyridine-2-carbaldehyde thiosemicarbazone and HPTSC* = pyridine-2-carbaldehyde 4N-methylthiosemicarbazone), and their complexes with different transition metal ions as Cu(II), Fe(III) and Co(III), have antitumor activity in colon cancer cells (HT-29 and SW-480), that have different oncogenic characteristics. Cytotoxicity was evaluated and the involvement of oxidative stress in its mechanism of action was analyzed by quantifying the superoxide dismutase activity, redox state by quantification of the thioredoxin levels and reduced/oxidized glutathione rate and biomolecules damage. The apoptotic effect was evaluated by measurements of the levels of caspase 9 and 3 and the index of histones. All the metal-thiosemicarbazones have antitumor activity mediated by oxidative stress. The HPTSC*-Cu was the compound that showed the best antitumor and apoptotic characteristics for the cell line SW480, that is KRAS gene mutated.

Thiosemicarbazones (TSCs), and their copper derivatives, have been extensively studied mainly due to the potential applications as antitumor compounds. A part of the biological activity of the TSC-CuII complexes rests on their reactivity against cell reductants, as glutathione (GSH). The present paper describes the structure of the [Cu(PTSC)(ONO2)]n compound (1) (HPTSC =pyridine-2-carbaldehyde thiosemicarbazone) and its spectroscopic and magnetic properties. ESI studies performed on the reaction of GSH with 1 and the analogous [{Cu (PTSC*)(ONO2)}2] derivative (2, HPTSC* =pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) show the absence of peaks related with TSC-Cu-GSH species. However GSH-Cu ones are detected, in good agreement with the release of CuI ions after reduction in the experimental conditions. The reactivity of 1 and 2 with cytochrome c and myoglobin and their activities against HT-29 and SW-480 colon carcinoma cell lines are compared with those shown by the free HPTSC and HPTSC* ligands., Obra Social “la Caixa” (OSLC-2012-007), Ministerio de Economía y Competitividad and FEDER funds (CTQ2013-48937-C2-1-P, CTQ2015-70371-REDT, MAT2015-66441-P, BIO2015-67358-C2-2-P), Junta de Castilla y León (BU237U13), Gerencia Regional de Salud, Consejería de Sanidad, Junta de Castilla y León (GRS 1023/A/14), the Basque Government (project IT-779-13)

New thiosemicarbazonecopper(II) compounds with formulae [{Cu(L′)Cl}2] 1, [{Cu(L′)I}2] 2, [{CuL(H 2O)}2](SiF6)·4H2O 3, [{Cu(L′)(H2O)}2][Cu(L′)(H2O) 2]2-(SiF6)2·8H2O 4, Cu(HL)(SiF6)·4H2O 5, {Cu(HL)(H 2O)(SiF6)}n·nH2O 6 and Cu(HL′)(SiF6)·3H2O 7 have been synthesized and characterised, (HL = 2-pyridinecarbaldehyde thiosemicarbazone, and HL′ = 2-pyridinecarbaldehyde 4N-methylthiosemicarbazone). X-ray structural analyses on 1, 2, 3, 4 and 6 reveal that π-π stacking, anion-π and hydrogen bond interactions are present. The latter gives raise to helical chains (3) and hexameric clusters (4) of water molecules. The formation of S-bridged or X-bridged dimers is discussed. The magnetic properties of compounds 1-4 are shown. The influence of the electronegativity of the ancillary ligands, the anionic vs. neutral nature and the substituents in the thiosemicarbazone, together with the absence of inversion centres are studied in the S-bridged dimers, as models for other [Cu2(μ-SR)2] magnetic systems. © 2014 Elsevier Ltd. All rights reserved., This work has been carried out with the financial support of the Ministerio de Ciencia e Innovación. CTQ2010-15358, Junta de Castilla y León BU237U13 and GR172 Projects and the Basque Government IT-779–13 and MINECO CTQ2013-48937-C2- 1-P and MAT2012-34740 Projects. The Universidad de Burgos and Caja de Burgos, Spain, are also gratefully acknowledged. R. G.–G. wishes to thank to the Junta de Castilla y León for his Doctoral Fellowship

New thiosemicarbazonecopper(II) compounds with formulae [{CuL(H 2O)}{CuL(SO4)}]·H2O 1, [{CuL(H 2O)}{CuL(SO4)}]n·nH2O 2 and [Cu(HL′)(SO4)(H2O)]·0.75H2O 3, (HL = pyridine-2-carbaldehyde thiosemicarbazone, and HL′ = pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) have been synthesized and characterized by elemental analysis, FAB+ mass spectrometry, infrared spectroscopy, electron paramagnetic resonance and thermal analysis. In addition, the preparation of the previously published [{Cu(L′)(H 2O)}{Cu(L′)(SO4)}]·4H2O 4 compound has been optimized. The crystal structures of 1, 2 and 3 have been solved using X-ray diffraction measurements. The compound 3 is formed by monomeric entities, while 1 and 2 are structural isomers and give rise to dinuclear and 1D polymorphs, respectively. Magnetic measurements have been carried out on 1, 2, 4 and [{Cu(HL)(SO4)}2] 5, being the latter prepared by a different method to that already reported. The magnetic properties are discussed and compared with those of analogous thiosemicarbazonecopper(II) complexes. © 2013 Elsevier Ltd. All rights reserved., This work has been carried out with the financial support of the Ministerio de Ciencia e Innovación CTQ2010-15358 Project, the Junta de Castilla y León BU002A09 and GR172 Projects. The Universidad de Burgos and Caja de Burgos, Spain, are also gratefully acknowledged. R.G.-G. wishes to thank to the Junta de Castilla y León and the Fondo Social Europeo for his Doctoral Fellowship.

New polyoxometallate-thiosemicarbazone hybrid compounds derived from pyridine-2-carbaldehyde thiosemicarbazone (HL), pyridine-2-carbaldehyde N 4 -methylthiosemicarbazone (HL') and their copper(II) complexes have been synthesized. Their formulae are (H 2 L) 4 (Mo 8 O 26 )(H 2 O) 4 (1), [{(HL) 2 H} 2 (Mo 6 O 19 )]·C 3 H 6 O·0.24H 2 O (2), [(H 2 L') 4 (HL') 2 (Mo 8 -O 26 )(H 2 O) 2 ] (3), [{Cu(L)} 4 (Mo 8 O 26 )(H 2 O) 4 ] (4), [{Cu(HL)(H 2 O)} 2 -(Mo 8 O 26 )] (5), [{Cu(L')} 4 (Mo 8 O 26 )(H 2 Oh 4 ] (6), Na 6 [{CU-(HL')(H 2 O) 2 } 4 ({Cu(L')} 2 {Mo 36 O 116 (H 2 O) 12 })]·20H 2 O (7), [(Cu-(HL)} 2 [Cu(L)} 4 {Mo 36 O 112 (H 2 O) 16 }(H 2 O) 26 ] ( 8 ), [{Cu(HL')} 4 -{Mo 36 O 112 (H 2 O) 16 }(H 2 O) 30 ] (9) and [{Cu(HL)(H 2 O)} 2 {Cu(L)-S} 2 (H 4 V 10 O 28 )] n ·6nH 2 O (10). Compounds 1-6 contain octa-molybdate [Mo 8 O 26 ] 4- or hexamolybdate [M o6 O 19 ]1 2- anions together with (H 2 L) + , (H 2 L') + , [Cu(L)] + , [Cu(HL)(H 2 O)] 2+ or [Cu(L')] + cations and neutral thiosemicarbazone molecules. The polyoxometallates (POMs) in 7-9 are [Mo 36 O 116 -(H 2 O) 12 ] 16- , {Mo 36 } (7), and [Mo 36 O 112 (H 2 O) 16 ] 8- , {Mo 36 '} (8, 9). [Cu(HL')] 2+ /[Cu(L')] + and [Cu(HL)] 2+ /[Cu(L)] + units complete the respective lattices. Compound 10 consists of decavanadate anions (H 4 V 10 O 28 ) 2- and thiosemicarbazone-copper(II) entities forming 1D [{Cu(HL)(H 2 O)} 2 {Cu(L)S} 2 -(H 4 V 10 O 28 )] n structures connected through the hydrogen bonds of chains of water molecules. Structures of 2, 5, 7 and 10 have been characterized by single-crystal X-ray diffraction and other instrumental techniques (infrared, thermal analysis, electron paramagnetic resonance, nuclear magnetic resonance, magnetic susceptibility and mass spectrometry) were used to analyse all the compounds presented herein. The structural parameters of more than 1000 published thiosemicarbazone-metal complexes have been used to determine some of the differences between metal complexes that contain anionic and neutral thiosemicarbazone ligands.

The interaction of the Cu(II) drugs CuL(NO(3)) and CuL'(NO(3)) (HL is pyridine-2-carbaldehyde thiosemicarbazone and HL' is pyridine-2-carbaldehyde 4N-methylthiosemicarbazone, in water named [CuL](+) and [CuL'](+)) with [poly(dA-dT)](2), [poly(dG-dC)](2), and calf thymus (CT) DNA has been probed in aqueous solution at pH 6.0, I = 0.1 M, and T = 25 degrees C by absorbance, fluorescence, circular dichroism, and viscosity measurements. The results reveal that these drugs act as groove binders with [poly(dA-dT)](2), with a site size n = 6-7, whereas they act as external binders with [poly(dG-dC)](2) and/or CT-DNA, thus establishing overall electrostatic interaction with n = 1. The binding constants with [CuL'](+) were slightly larger than with [CuL](+). The title compounds display some cleavage activity in the presence of thiols, bringing about the rupture of the DNA strands by the reactive oxygen species formed by reoxidation of Cu(I) to Cu(II); this feature was not observed in the absence of thiols. Mutagenic assays performed both in the presence and in the absence of S9 mix, probed by the Ames test on TA 98, TA 100, and TA 102, were negative. Weak genotoxic activity was detected for [CuL](+) and [CuL'](+), with a significative dose-response effect for [CuL'](+), which was shown to be more cytotoxic in the Ames test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assays. Methylation of the terminal NH(2) group enhances the antiproliferative activity of the pyridine-2-carbaldehyde thiosemicarbazones.

The work presented here describes the synthesis of new copper(II) complexes derived from 2-amino-5-(pyridin-2-yl)-1,3,4-oxadiazole (L1) and 2-methylamino-5-(pyridin-2-yl)-1,3,4-oxadiazole (L2) which also incorporate azido (N3 -), thiocyanato (NCS-), cyanato (NCO-), dicyanamido [N(CN)2 -, dca] and malonato (C3H2O4 2-, mal) coligands. Structures of the [Cu(L2)(mal)(H2O)]·2H 2O(1), [{Cu(L2)(mal)}2] (2), [Cu(L 2)2-(NCS)2] (3), [Cu(L1)(NCS) 2]n (4) and [{Cu(L2)}2(dca) 2](ClO4)2·2H2O (5) compounds show the dependence of the dimensionality on parameters such as the type of oxadiazole and coligand utilised, solvents or reaction times. In this sense, 1 and 3 are mononuclear complexes, 2 contains centrosymmetric dinuclear entities, 4 is a 1D compound in which thiocyanato groups act as end-to-end bridges and 5 shows a 2D arrangement of dinuclear motifs linked through dicyanamido spacers. The copper(II) ions acquire distorted octahedral (3 and 4), square-pyramidal (1 and 2) and trigonal bipyramidal (5) geometries. Stacking π-π interactions and hydrogen bonds stabilise the crystal frameworks. Water tetramers are present in 1. Spectroscopic (infrared, UV/Vis absorption and electron spin resonance) studies have also been developed for 1-5 and for the Cu(L2)(dca) 2(H2O) (6), Cu(L2)(NCO)2 (7) and Cu(L2)2(N3)2(H2O) 2 (8) complexes. The studies suggest the coordination of oxadiazole and coligands in all cases. Magnetic measurements show antiferromagnetic coupling for compound 5, ferromagnetic interactions for compound 2 and paramagnetic behaviour in compound 4. The susceptibility data were fitted by using the Bleaney-Bowers' equation for the copper(II) dimers derived from H = -2JS1S2. The resultant J/k values are +2.15 and -38.3 K for compounds 2 and 5, respectively. Magneto-structural correlations are discussed and extended to more than 30 published dinuclear Cu(NN) 2Cu′ diazole-only bridged compounds. All these systems show J values close to or greater than those given by the expression J ≈ -90 + 3 Δβ (where Δβ is the difference between the Cu-N-N and Cu-N′-N′ angles). The artificial nuclease activity of 1, 2, 3 and 5 in the presence of mercaptopropionic acid or glutathione has also been analysed and compared with that exhibited by [Cu(L2)2(H 2O)2](NO3)2 and CuSO4. © Wiley-VCH Verlag GmbH & Co. KGaA, 2009., We thank Dr. J. J. Delgado (SCAI, Universidad de Burgos, Spain) for the elemental analyses and Prof. R. Olazcuaga and Dr. F. Guillen (CNRS, Pessac, France) for the reflectance measurements. This work was financially supported by the Junta de Castilla y Leon (BU033A06) and Ministerio de Ciencia y Tecnologia (MCYT) [CTQ2007-63690 (ERDF(EU)-DGI-MCYT)]. P. G.-S. thanks the Universidad de Burgos for a Doctoral Fellowship.

Experimental studies of the binding interactions of [CuL(NO 3 )] and [{CuL′(NO 3 )} 2 ] (HL = pyridine-2-carbaldehyde thiosemicarbazone, and HL′ = pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) with adenine, guanine, cytosine, thymine and their mononucleotides ( d NMP), 2-deoxyadenosine-5′-monophosphate, ( d AMP), 2′-deoxyguanosine-5′-monophosphate, ( d GMP), 2′-deoxycytidine-5′-monophpsphate ( d CMP), and thymidine-5′-monophosphate ( d TMP) have been carried out in aqueous solution at pH 6.0, I = 0.1 M (NaClO 4 ) and T = 25 °C. The complexation constants of these compounds, calculated by Hildebrand–Benesi plots for the dye binding, D , ([CuL] or [CuL′]) to the nucleobases or nucleotides (P), have shown two linear stretches in adenine, guanine, d AMP and d GMP. The data were analyzed in terms of formation of 1:1 DP and 1:2 DP 2 complexes with increasing purine base or nucleotide content. For cytosine and d CMP only 1:1 complexes have been observed, whereas for thymine and d TMP such complex structures were not observed. The [CuL(Hcyt)](ClO 4 ) cytosine derivative has been isolated and characterized. The crystal structure consists of perchlorate ions and [CuL(Hcyt)] + monomers attached by hydrogen bond, chelate π−ring and anion–π interactions. The Cu 2+ ions bind to the NNS chelating moiety of the thiosemicarbazone ligand and the cytosine N13 site (N3, most common notation) yielding a square-planar geometry. A pseudocoordination to the cytosine O12 site (=O2) can also be considered.

Unusual species are obtained from the HL/CuII/NO3– system (HL = pyridine-2-carbaldehyde thiosemicarbazone) in basic aqueous solutions. A partial desulfurization process occurs for 1:1 Cu/HL molar ratio which gives rise to the precipitation of the mixed ligand [Cu(L)(LCN)] (1) complex [HLCN = C7H6N4, (pyridin-2-ylmethylene)hydrazinecarbonitrile]. This compound contains CuII ions in a square-pyramidal environment. On the other hand, distorted octahedral [Cu(L)2] (2) entities are isolated in excess of the thiosemicarbazone ligand. Desulfurization of the thiosemicarbazone is detected even at physiological pH values. However, this reaction does not take place in absence of CuII ions, and HL·2.25H2O (3) or HL·H2O are obtained in these conditions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

A basic aqueous solution of the [{Cu(L)(NO3)}2] compound (HL = C8H10N4S, pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) at pH = 11 is acidified to pH = 5 by addition of diluted nitric acid yielding the [{Cu(L)}2(NO3)](OH) · 5H2O (1) complex. The structure of 1 contains a bidentate Cu–ON(O)O–Cu nitrato bridge. However, a 1:2 copper:thiosemicarbazone ratio in the Cu II / HL / NO 3 - system leads to the attainment of the [{Cu(L)(H2O)}{Cu(L)(SO4)}] · 5H2O (2) compound. The monodentate sulfato group in 2 arises from the desulfurization of thiosemicarbazone ligands. In both cases, the crystal structures consist of dinuclear non-centrosymmetric entities where the thiosemicarbazone sulfur atoms act as bridges between copper(II) ions in distorted square-pyramidal environments.

Estudios estructurales sobre entidades tiosemicarbazonacobre(II) y su interacción con polioxometalatos y biomoléculas. Síntesis, estabilidad y propiedades magnéticas” El presente Trabajo ahonda en la síntesis y caracterización de nuevos derivados de Cu(II) con los ligandos 2–piridinacarbaldehído tiosemicarbazona (HL) y 2–piridinacarbaldehído N4–metiltiosemicarbazona (HLM). En ellos, las entidades tiosemicarbazonacobre(II) se enlazan a iones inorgánicos sencillos (cloruro, perclorato, sulfato y hexafluorurosilicato), polioxometalatos (aniones hexamolibdato, octamolibdato y decavanadato entre otros) y biomoléculas (tioles celulares, nucleobases y nucleótidos). Su estudio químico y estructural ha permitido establecer ciertas relaciones que ayudan a comprender mejor algunas de sus propiedades espectroscópicas y magnéticas, así como su actividad biológica. Finalmente, se proporcionan evidencias estructurales para ciertos tipos de roturas del ligando tiosemicarbazona, que ayudan a conocer mejor en qué condiciones estas especies son estables en disolución y en cuáles tienen lugar diversos procesos de descomposición.

New complexes of formulae [Cu(HL 2 )(H 2 O)(NO 3 )](NO 3 ) ( 1 ), [{Cu(L 1 )(tfa)} 2 ] ( 2 ), [{Cu(L 1 )} 2 (pz)](ClO 4 ) 2 ( 3 ) and {[{Cu(L 1 )} 2 (dca)](ClO 4 )} n ( 4 ), where HL 1 = pyridine-2-carbaldehyde thiosemicarbazone, HL 2 = pyridine-2-carbaldehyde 4 N -methylthiosemicarbazone, Htfa = trifluoroacetic acid (CF 3 COOH), pz = pyrazine (C 4 H 4 N 2 ) and dca = dicyanamide [N(CN) 2 ] − , have been synthesized and characterized. The crystal structures of these compounds are built up of monomers ( 1 ), dinuclear entities with the metal centers bridged through the non-thiosemicarbazone coligand ( 2 and 3 ) and 1D chains of dimers ( 4 ). In all the cases, square–pyramidal copper(II) ions are present, except for the square–planar ones in 3 . Magnetic measurements show antiferromagnetic couplings in 2, 3 and 4 . The susceptibility data were fitted by the Bleaney–Bowers’ equation for copper(II) dimers derived from H = –2 JS 1 S 2 being the obtained J/k values −4.8, −4.3 and −5.1 K for compounds 2 – 4 , respectively. The magnetic susceptibility of the already known [{Cu(HL 1 )(tfa)} 2 ](tfa) 2 compound has been also measured for the first time. The J/k value is –0.3 K, lower than that in 2 . The nuclease activity of 3 and 4 has been analyzed.