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Complexes [In(2Ac4oFPh)Cl2(MeOH)] (1) and [In(2Ac4oFPh)Cl2]·0.5EtOH (2) were obtained with 2-acetylpyridine-N(4)-ortho-fluorophenyl thiosemicarbazone (H2Ac4oFPh). Neutron activation of 1 and 2 resulted in the formation of the 114mIn/115mIn analogues (*1) and (*2). The thiosemicarbazone ligand, the non-radioactive and radioactive complexes were assayed for their cytotoxic effects against U87 human glioblastoma cells. While radioactive and non-radioactive InCl3 were devoid of cytotoxic activity, complexes (1) and (2) and their radioactive analogues (*1) and (*2) showed similar cytotoxic effects and were as active as the parent thiosemicarbazone against U87 glioma cells. Since the radioactive complexes revealed to keep the thiosemicarbazone cytotoxicity, if these complexes are produced with high specific activity, they might constitute an interesting platform for the development of prototype radiotracer drugs for treatment of glioma neoplasia by delivering high radiation dose to the tumor cells.

4-[bis(2-chloroethyl)amino]benzaldehyde-N(4)-phenyl-thiosemicarbazone (1), 4-[bis(2-chloroethyl)amino]benzaldehyde-N(4)-para-chloro-phenyl-thiosemicarbazone (2), 4-[bis(2-chloroethyl)amino]benzaldehyde-N(4)-methyl-thiosemicarbazone (3) and 4-[bis(2-chloroethyl)amino]benzaldehyde-benzoylhydrazone (4) were obtained by functionalization of the bis(2-chloroethyl)amino DNA alkylating group with a thiosemicarbazone/hydrazone moiety. The compounds were fully characterized by means of their infrared (including theoretical vibrational analyses) and NMR spectra, as well as by means of X-ray crystal structure determinations. When assayed on a panel of different tumor cells only (1) exhibited cytotoxic effects on B16F10 melanoma cells (IC50 = 17.1 ± 3.1 μM). A cell viability assay on melanoma cells revealed that while (1) had cytotoxic effects on B16F10 and A2058 cells, the structure-related hydrazone (4) was devoid of activity. In addition, (1) was capable to reduce viability of melanoma cells without affecting the viability of non-malignant human endothelial cells (HUVEC), suggesting that this compound or its analogues could be further investigated as potential antimelanoma drug candidates. Preliminary investigation on the mode of action of (1) indicated that the compound induces cell death by necrosis. Theoretical calculations showed that in all compounds (1–4) the reactivities of the N-mustard pharmacophoric group towards dehalogenation are similar. In addition, theoretical studies suggested that the nucleophilicities of the mustard group are very similar in (1–4). Hence, all compounds (1–4) might be expected to exhibit comparable reactivity, and the differences in biological activity among the compounds may not be attributed to variances in reactivity at the N-mustard group.

Herein we describe the syntheses of 4-(2-nitrophenylsulfonamido)benzoic acid (HL), and its tri-n-butyltin(IV) complex, Bu3SnL. The compounds were characterized by elemental analyses, FT-IR, 1H NMR, 13C{1H} NMR and X-ray diffraction. For the complex 119Sn{1H} NMR and 119Sn Mossbauer spectroscopies were also employed. The Bu3SnL is a monomer in the solid and solution states but exists as a polymer in the crystalline structure. The complex adopted distinct geometries, being tetrahedral in solution and intermediate between tetrahedral and trigonal bipyramidal in the solid state. Crystal structure determination of Bu3SnL revealed a bipyramid-trigonal geometry around the metal center, and the presence of a polymeric structure sustained by carboxylate bridges. Interconnections in the crystal structures were analyzed using Hirshfeld surfaces. The 2D-fingerprint plots indicated that the O H/H O interactions are more frequent in the HL·H2O crystal packing (44.9%) than in the Bu3SnL (26.8%).

Cobalt(III) complexes [Co(L1)2]Cl·CH3OH·0.5H2O (1), [Co(L2)2]Cl·1.5H2O (2), [Co(L3)2]Cl·2H2O (3) and [Co(L4)2]Cl·3.5H2O (4) were obtained with 2-acetylpyridine-N(4)-phenylthiosemicarbazone (HL1), 2-acetylpyridine-N(4)-para-chlorophenylthiosemicarbazone (HL2), 2-acetylpyridine-phenylhydrazone (HL3) and 2-acetylpyridine-para-chlorophenylhydrazone (HL4). The complexes were characterized by means of microanalyses, molar conductivities and their infrared and 1H and 13C NMR spectra. Electrochemical studies showed that the CoIII/CoII reduction potential of complexes (3) and (4) but not of complexes (1) and (2) are suitable for the compounds to be reduced by cellular reductants. Reactivity assays showed that complex (3) undergoes reduction by sodium dithionite with subsequent ligand release. The results suggested that coordination of 2-acetylpyridine-derived hydrazones with cytotoxic activity to cobalt(III) results in compounds which are able to release the bioactive ligand upon reduction. In addition, the cobalt(III) complexes under study interacted with human serum albumin (HSA), indicating that they could be transported by this protein.

Complexes [ReCl(CO)3(H2AcPh)] (1), [ReCl(CO)3(H2AcpClPh)]·0.5C7H8 (2) and [ReCl(CO)3(H2AcpNO2Ph)]·0.5C7H8 (3) were obtained with 2-acetylpyridine-phenylhydrazone (H2AcPh) and its para-chlorophenylhydrazone (H2AcpClPh) and para-nitrophenylhydrazone (H2AcpNO2Ph) analogues. Coordination to tricarbonylrhenium(I) resulted in a higher antiproliferative activity against NCI-H460 human large cell lung cancer. Complexes (2) and (3) induced apoptosis on NCI-H460 cells. Complex (2) induced mitochondrial damage while treatment with 3 showed a later response, suggesting that probably the same effect would be observed at higher concentrations or longer treatments. Both complexes (2) and (3) showed a high antioxidant activity, 2 being more potent in reducing intracellular reactive oxygen species (ROS) production.

The nuclease activity and the cytotoxicity toward human leukemia cancer cells of iron complexes, [Fe(HPClNOL)Cl2]NO3 (1), [Cl(HPClNOL)Fe(μ-O)Fe(HPClNOL)Cl]Cl2·2H2O (2), and [(SO4)(HPClNOL)Fe(μ-O)Fe(HPClNOL)(SO4)]·6H2O (3) (HPClNOL=1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol), were investigated. Each complex was able to promote plasmid DNA cleavage and change the supercoiled form of the plasmid to circular and linear ones. Kinetic data revealed that (1), (2) and (3) increase the rate of DNA hydrolysis about 278, 192 and 339 million-fold, respectively. The activity of the complexes was inhibited by distamycin, indicating that they interact with the minor groove of the DNA. The cytotoxic activity of the complexes toward U937, HL-60, Jukart and THP-1 leukemia cancer cells was studied employing 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), fluorescence and electronic transmission microscopies, flow cytometry and a cytochrome C release assay. Compound (2) has the highest activity toward cancer cells and is the least toxic for normal ones (i.e. peripheral blood mononuclear cells (PBMCs)). In contrast, compound (1) is the least active toward cancer cells but displays the highest toxicity toward normal cells. Transmission electronic microscopy indicates that cell death shows features typical of apoptotic cells, which was confirmed using the annexin V-FITC/PI (fluorescein isothiocyanate/propidium iodide) assay. Furthermore, our data demonstrate that at an early stage during the treatment with complex (2) mitochondria lose their transmembrane potential, resulting in cytochrome C release. A quantification of caspases 3, 9 (intrinsic apoptosis pathway) and caspase 8 (extrinsic apoptosis pathway) indicated that both the intrinsic (via mitochondria) and extrinsic (via death receptors) pathways are involved in the apoptotic stimuli.

Complexes [Au(PyCT4BrPh)Cl]Cl (1), [Pt(PyCT4BrPh)Cl]0.5KCl (2), and [Pd(PyCT4BrPh)Cl]KCl (3) were obtained with 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4BrPh). Although complexes (2) and (3) did not exhibit potent cytotoxic activity, HPyCT4BrPh and its gold(III) complex (1) proved to be highly cytotoxic against HL-60 (human promyelocytic leukemia) and THP-1 (human monocytic leukemia) cells, and against MDA-MB 231 and MCF-7 (human breast adenocarcinoma) solid tumor cells. Except for HL-60 cells, upon coordination to gold(III) a 2- to 3-fold increase in the cytotoxic effect was observed. An investigation on the possible biological targets of the gold(III) complex was carried out. Complex (1) but not the free thiosemicarbazone inhibits the enzymatic activity of thioredoxin reductase (TrxR). The affinity of 1 for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. While HPyCT4BrPh was inactive, 1 was able to inhibit topoisomerase IB (Topo IB) activity. Hence, inhibition of TrxR and Topo IB could contribute to the mechanism of cytotoxic action of complex (1).

This is a review article on non-radioactive gallium(III) complexes as new promising metal-based drug candidates. A great variety of gallium(III) complexes and their pharmacological applications as anticancer and antimicrobial agents are described together with possible biological targets and modes of action.

Complexes [Sb(2Ac4oClPh)Cl2] (1), [Sb(2Ac4oFPh)Cl2] (2), [Sb(2Ac4oNO2Ph)Cl2] (3), [Sb(2Bz4oClPh)Cl2] (4), [Sb(2Bz4oFPh)Cl2] (5) and [Sb(2Bz4oNO2Ph)Cl2] (6) were obtained with 2-acetylpyridine-N(4)-ortho-chlorophenyl thiosemicarbazone (H2Ac4oClPh) and its N(4)-ortho-fluor (H2Ac4oFPh) and N(4)-ortho-nitro (H2Ac4oNO2Ph) analogues, and with the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2Bz4oFPh, H2Bz4oNO2Ph). The studied compounds are excellent inhibitors of Trypanosoma cruzi growth. H2Bz4oClPh and complexes (4) and (1) were the most trypanosomicidal. Upon coordination of H2Ac4oClPh to antimony(III) in 1, the therapeutic index (TI) goes from 10.58 to 14.35. However, the best values of TI were found for H2Bz4oClPh (TI = 1240) and H2Ac4oNO2Ph (TI = 773). Structure–activity relationship (SAR) studies did not allow the establishment of correlations between the anti-trypanosomal activity and physico-chemical parameters, but correlations were found between the cytotoxicities and physico-chemical properties.

Complex [Bi(Lp)(2)]Cl was obtained with 4-hydroxy-3-(3-methylbut-2-enyl)naphthalene-1,2-dione, "lapachol" (HLp). Lapachol, [Bi(Lp)(2)]Cl and BiCl(3) were evaluated in a murine model of inflammatory angiogenesis induced by subcutaneous implantation of polyether polyurethane sponge discs. Intraperitoneal (i.p.) administration of lapachol or [Bi(Lp)(2)]Cl reduced the hemoglobin content in the implants suggesting that reduction of neo-vascularization was caused by lapachol. In the per os treatment only [Bi(Lp)(2)]Cl decreased the hemoglobin content in the implants. Likewise, N-acetylglucosaminidase (NAG) activity decreased in the implants of the groups i.p. treated with lapachol and [Bi(Lp)(2)]Cl while in the per os treatment inhibition was observed only for [Bi(Lp)(2)]Cl. Histological analysis showed that the components of the fibro-vascular tissue (vascularization and inflammatory cell population) were decreased in lapachol- and complex-treated groups. Our results suggest that both lapachol and [Bi(Lp)(2)]Cl exhibit anti-angiogenic and anti-inflammatory activities which have been attributed to the presence of the lapachol ligand. However, coordination to bismuth(III) could be an interesting strategy for improvement of lapachol's therapeutic properties.

Salicylaldehyde 2-chlorobenzoyl hydrazone (H 2LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H 2LASSBio-1064) and their complexes [Zn(LASSBio- 466)H 2O] 2 (1) and [Zn(HLASSBio-1064)Cl] 2 (2) were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acid-induced writhing response. Upon coordination the antinociceptive activity was favored in the complex 1. H 2LASSBio-466 inhibited only the first phase of the formalin test, while 1 was active in the second phase, like indomethacin, indicating its ability to inhibit nociception associated with the inflammatory response. Hence coordination to zinc(II) altered the pharmacological profile of H 2LASSBio-466. H2LASSBio-1064 inhibited both phases but this effect was not improved by coordination. The studied compounds did not increase the latency of response in the hot plate model, indicating their lack of central anti-nociceptive activity. All compounds showed levels of inhibition of zymosan-induced peritonitis comparable or superior to indomethacin, indicating an expressive anti-inflammatory profile., Facultad de Ciencias Exactas

Complexes [Zn2(HL1)2(CH3COO)2] (1) and [Zn2(L2)2] (2) were synthesized with salicylaldehyde semicarbazone (H2L1) and salicylaldehyde-4-chlorobenzoyl hydrazone (H2LASSBio-1064, H2L2), respectively. The crystal structure of (1) was determined. Upon recrystallization of previously prepared [Zn2(HL2)2(Cl)2] (3) in 1:9 DMSO:acetone crystals of [Zn2(L2)2(H2O)2]·[Zn2(L2)2(DMSO)4] (3a) were obtained. The crystal structure of 3a was also determined. All crystal structures revealed the presence of phenoxo-bridged binuclear zinc(II) complexes.

[(n-Bu)Sn(2Ac4oClPh)Cl2] (1), [(n-Bu)Sn(2Ac4oFPh)Cl2] (2), [(n-Bu)Sn(2Ac4oNO2Ph)Cl2] (3), [(n-Bu)Sn(2Bz4oClPh)Cl2] (4), [(n-Bu)Sn(2Bz4oFPh)Cl2] (5) and [(n-Bu)Sn(2Bz4oNO2Ph)Cl2] (6) were obtained by reacting [(n-Bu)SnCl3] with 2-acetylpyridine-N4-orthochlorophenyl thiosemicarbazone (H2Ac4oClPh), 2-acetylpyridine-N4-orthofluorphenyl thiosemicarbazone (H2Ac4oFPh), 2-acetylpyridine-N4-orthonitrophenyl thiosemicarbazone (H2Ac4oNO2Ph), and with the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2ABz4oFPh and H2Bz4oNO2Ph). The antifungal activity of the studied compounds was evaluated against several Candida species. Upon coordination of H2Bz4oNO2Ph to tin in complex (6) the antifungal activity increased three times against Candida albicans and Candida krusei and six times against Candida glabrata and Candida parapsilosis. The minimum inhibitory concentration (MIC) values of H2Ac4oNO2Ph and its complex (3) against C. albicans, C. parapsilosis and C. glabrata are similar to that of fluconazole. All studied compounds were more active than fluconazole against C. krusei.

The reaction of FeSO4 · 7H2O with the ligand HPClNOL (1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol results in the complex [Fe(HPClNOL)(SO4)]2-μ-oxo · 6H2O 1, in which the iron ions are coordinated by two pyridines, one amine and one alcohol group from the ligand HPClNOL, an oxo bridge and monodentate sulfate ion. The complex is highly soluble in water and potentiometric titration experiments reveal four protonation/deprotonation equilibria, with pKa values of 2.77(3), 4.34(6), 8.07(4) and 8.58(8). The nuclease activity of complex 1 was evaluated at pH 7.0, 8.0 and 9.0. Complex 1 was able to promote single and double strand DNA cleavage in both aerobic and anaerobic condition, indicating that the cleavage process should follow a hydrolytic mechanism.

The use of monooxygenase biomimetic catalysts has demonstrated good efficiency in the hydrocarbon oxidation. In this work we have used the complex [Fe III (HBPClNOL)(Cl) 2 ]·H 2 O as catalyst in the cyclohexane oxidation and the products cyclohexanol, cyclohexanone and adipic acid were obtained. Cyclohexyl hydroperoxide and the tert -butyl cyclohexyl peroxide were also obtained as byproducts. The best reaction condition was reached with the system H 2 O 2 –acetonitrile at 50 °C, with 26.9% of yield. The investigation of the catalysis over time showed that the yields increase until 24 h, although the reaction rate is greater in the first 6 h. The electronic spectra of the complex were measured during the cyclohexane oxidation and it was possible to verify the disappearance of the bands assigned to the charge transfer from the phenolate and the chloride ligands to the iron. This indicates that electronic and/or structural changes are happening with the iron compound, confirming the existence of interaction between the complex and the oxidant.

We present here the synthesis, crystal structure, electrochemical behavior, spectroscopic properties (FT-IR, UV–Vis and EPR), nuclease and in vitro antitumor activities against human myeloid leukemia cell line of the mononuclear copper complex [Cu(HPClNOL)(Cl)]Cl · MeOH (1). The reaction of the tetradentate ligand HPClNOL [1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol] and 1 equiv. of [Cu(OH2)6](Cl)2, in methanol, resulted in 1, which crystallizes as blue monoclinic crystals. The complex is pentacoordinated with a distorted square-pyramidal geometry. The activity of complex 1 toward plasmid DNA and THP-1 carcinogenic cells was investigated. Complex 1 promotes the cleavage of supercoiled DNA (pBlueScript KS+ DNA) to nicked circular and linear DNA forms. In addition to the three typical KS+ DNA forms, the cleavage resulted in a fourth band, which was visualized above of the nicked circular form. The results reveal that the cleavage mechanism is radical-independent. Furthermore, complex 1 is able to promote cell death of THP-1 cells by apoptosis, as confirmed by fluorescent microscopy, cell morphology and DNA degradation.

Metal complexes with 2-acetylpyridine-N(4)-orthochlorophenylthiosemicarbazone (H2Ac4oClPh) were assayed for their cytotoxicity against MCF-7 breast adenocarcinoma and HT-29 colon carcinoma cells. The thiosemicarbazone and most of the complexes were highly cytotoxic. H2Ac4oClPh and its gallium(III) and tin(IV) complexes did not show any inhibitory activity against thioredoxin reductase (TrxR) and glutathione reductase (GR). The palladium(II), platinum(II) and bismuth(III) complexes inhibited TrxR at micromolar concentrations but not GR. The antimony(III) and gold(III) complexes strongly inhibited TrxR at submicromolar doses with GR inhibition at higher concentrations. The selectivity of these complexes for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. TrxR inhibition is likely a contributing factor to the mode of action of the gold and antimony derivatives.

The development of metallodrugs with antioxidant activities is of importance as a way to protect organisms exposed to stressful conditions. Although iron chemistry in the presence of H(2)O(2) is usually associated with pro-oxidant activity, mainly via the Fenton reaction, we found that the mononuclear compound [Fe(HPClNOL)Cl(2)]NO(3) (1; C(15)H(18)Cl(3)FeN(4)O(4), a = 8.7751(3) A, b = 9.0778(4) A, c = 24.3869(10) A, beta = 93.370(2) degrees , monoclinic, P2(1)/c, Z = 4), containing the tripodal ligand 1-[bis(pyridin-2-ylmethyl)amino]-3-chloropropan-2-ol, decomposes hydrogen peroxide and superoxide anion in vitro as well as shows in vivo protection because it prevents the harmful effects promoted by H(2)O(2) on Saccharomyces cerevisiae cells, decreasing the level of lipid peroxidation. This protective effect was observed for wild-type cells, as well as for mutant cells, which do not present the antioxidant metalloenzymes catalase (Ctt1) or copper/zinc superoxide dismutase (Sod1).

2-Acetylpyridine-phenylhydrazone (H2AcPh), its para-chlorophenylhydrazone (H2AcpClPh) and para-nitrophenylhydrazone (H2AcpNO2Ph) analogues, the corresponding 2-benzoylpyridine-derived hydrazones (H2BzPh, H2BzpClPh and H2BzpNO2Ph) and their gallium(III) complexes were assayed for their cytotoxic activity against U87 (expressing wild-type p53 protein) and T98 (expressing mutant p53 protein) glioma cells. IC50 values against both glioma cells and against the MRC5 (human fetal lung fibroblast) lineage were obtained for the hydrazones, but not for their gallium(III) complexes, due to their low solubility. Hydrazones were highly cytotoxic at nanomolar doses against U87 and T98 cells. The therapeutic indexes (TI = IC50MRC5/IC50glioma) were 2-660 for T98 cells and 28-5000 for U87 cells, indicating that the studied hydrazones could be good antitumor drug candidates to treat brain tumors.

We report herein the synthesis and characterization of two dinuclear μ-oxo iron compounds obtained through the reactions of FeSO4•7H2 O and FeCl3•6H2 O with 1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol (L5), which resulted in the compounds [(SO4)(L5)Fe(μ-O)Fe(L5)(SO4 )]•6H2O, 1, and [Cl(L5)Fe(μ-O)Fe(L5)Cl]Cl2• 2H2O, 2. The electronic spectra of both compounds show absorption bands only in the UV range. The electrochemical analysis showed that the dinuclear unit is more stable under reduction in compound 1 than in compound 2, while the Mössbauer spectroscopy revealed that the monodentate ligands (sulfate and chloride) have a significant influence on the Mössbauer parameters determined for 1 and 2, particularly on the quadrupole splitting values. Both compounds were studied as catalysts in reactions of cyclohexane oxidation, using H2O2 and t-BuOOH as oxidants, in a substrate:oxidant:catalyst ratio of 1000:1000:1. Cyclohexanol, cyclohexanone, cyclohexyl hydroperoxide, t-butyl cyclohexyl peroxide and adipic acid were formed during the process. The experiments revealed that compound 2 is, in general, more active than compound 1 in promoting cyclohexane oxidation. Neste artigo são apresentadas a síntese e a caracterização de dois compostos binucleares de ferro, os quais contêm uma ponte μ-oxo. Os compostos [(SO4)(L5)Fe(μ-O)Fe(L5)(SO4 )]•6H2O, 1, e [Cl(L5)Fe(μ-O)Fe(L5)Cl]Cl2• 2H2O, 2, foram obtidos nas reações entre 1-(bis-piridin-2-ilmetil-amino)-3-cloropropan-2-ol (L5) e os sais FeSO4•7H2 O e FeCl3•6H2 O, respectivamente. Os espectros eletrônicos dos complexos apresentam absorções somente na região do ultravioleta, sendo que a análise eletroquímica revelou que, após a formação da espécie FeIII FeII, a unidade binuclear do composto 1 é mais estável do que a do composto 2. Os ligantes monodentados (sulfato e cloreto) exercem influência sobre os parâmetros Mössbauer determinados para 1 e 2, particularmente sobre os desdobramentos de quadrupolo. Os compostos foram empregados como catalisadores em reações de oxidação do cicloexano, usando H2O2 e t-BuOOH como oxidantes em uma razão substrato:oxidante:catalisador de 1000:1000:1. Os resultados indicam que o composto 2 é um catalisador mais eficiente que o composto 1.