Julio J. Criado

Thiourea derivatives and their nickel(II) and platinum(II) complexes: antifungal activity

We have synthesized two thiourea derivatives of methyl anthranilate (1, 2) and their complexes with nickel (3) and platinum(II) (4). We have also prepared the complexes of nickel(II) with two benzoylthiourea derivatives (5, 6). The obtained compounds were characterized by elemental analysis, spectroscopic methods (FT-IR, UV-vis, NMR), mass spectrometry and thermal analysis. Compound 1, C(20)H(23)N(3)O(2)S, crystallizes in monoclinic space group P21/n, with Z=4, and unit cell parameters, a=8.8042(4) A, b=7.6608(3) A, c=28.834(2) A, alpha=gamma=90 degrees, beta=90.94(1) degrees. Compound 2, C(20)H(21)N(3)O(3)S, crystallizes in monoclinic space group P21/c, with Z=4, and unit cell parameters, a=7.7345(4) A, b=8.6715(4) A, c=29.113(2) A, alpha=gamma=90 degrees, beta=90.67(1) degrees. Compound 5, C(24)H(30)N(4)NiO(2)S(2), crystallizes in monoclinic space group P21/n, with Z=4, and unit cell parameters, a=10.4317(8) A, b=18.517(2) A, c=13.299(1) A, alpha=gamma=90 degrees, beta=104.53(1) degrees. Compound 6, C(25)H(28)Cl(2)N(4)NiO(4)S(2), crystallizes with a molecule of CH(2)Cl(2) in triclinic space group P-1, with Z=2, and unit cell parameters, a=10.362(1) A, b=11.849(2) A, c=12.536(2) A, alpha=90.04(2) degrees, beta=84.73(1) degrees, gamma=113.43(2) degrees. Compounds 1 and 2 show antifungal activity against the major pathogens responsible for important plant diseases (Botrytis cinerea, Colletotrichum fragariae, Fusarium oxysporum and Phoma betae). The antifungal activity is practically the same for morpholine and ethyl derivatives.

Chemistry of dithiocarbamate derivatives of amino acids. I: Study of some dithiocarbamate derivatives of linear α-amino acids and their nickel(II) complexes

Abstract The barium dithiocarbamate derivates of the α-amino acids glycine, DL-alanine, DL-2-amino- butyric acid, DL-norvaline and DL-norleucine have been synthesized. The crystal structure of the glycine derivative was determined. The anions were used to obtain the corresponding nickel(II) complexes in acid form. The complexes are diamagnetic, and coordination takes place in a near-square planar geometry around the Ni(II) ion through the sulphur atoms of the dithiocarbamate moiety, the structure having been confirmed by IR, 1 H NMR, UV-Vis spectroscopies and chemical analysis.

Au(III) complexes of tris-dithiocarbamate derivatives of α-amino acids: spectroscopic studies, thermal behaviour and antibacterial activity

Abstract The synthesis and characterization of new coordination compounds of Au(III), with dithiocarbamates derived from α-amino acids (DL-alanine, DL-valine, L-valine and DL-leucine) is reported. As single crystals were not synthesized, a large number of experimental techniques was used to accomplish a definitive characterization and determination of the structures of these compounds. The compounds are hexacoordinated, but diamagnetic, the structure thus corresponding to a distorted trigonal prism. Only one XPS S(2p) signal is recorded, indicating a symmetric dithiocarbamate moiety surrounding the metallic cation; two Au(4f) signals are recorded in all cases, due to Au(III) and Au(I), through reduction of the former in the spectrometer chamber. Results obtained by applying other techniques (FT-IR, Vis-UV, NMR, MS) support the above conclusions. Antibacterial activity against nine Gram+ and Gram− species has been studied for the gold salt, the ligands, the complexes and control antimicrobial agents. Only the gold complexes exhibit a larger activity than the reference compounds, against Streptococcus pneumoniae.

Thiourea derivatives of α-aminoacids. Synthesis and characterization of Ni(II), Cu(II) and Pt(II) complexes with l-valinate derivatives. Antifungal activity

Abstract The preparation of metal complexes with 2-[(3,3′-diethylthioureido)phenylmethylamino]-3-methylbutyric acid methyl ester, Hetv, or 3-methyl-2′-{[morpholine-4-carbothioylimino)phenylmethyl]amino}-butyric acid methyl ester, Hmtv, has been achieved. The complexes obtained with formulae of Ni(etv)2, Cu(mtv)2·2H2O and Pt(Hmtv)Cl2, were studied and characterized by elemental analysis, electrical conductivity in solution, IR and UV–VIS spectra, FAB+ and electron impact (EI) mass spectrometry, 1H- and 13C-NMR, ESR, magnetic susceptibility, atomic absorption spectrometry and thermal analysis. Their antifungal activity was studied against the plant pathogenic fungi Colletotrichum fragariae, Rhizoctonia solani and Phoma betae.

Novel chelates of Pd(II) dithiocarbamates. Spectroscopic studies and thermal behaviour

Abstract Complexes of Pd(II) with dithiocarbamate derived from α-amino acid (glycine, DL -alanine, DL -valine, L -valine and DL -leucine) have been synthesized. The complexes have been characterized by chemical analysis, infrared, electronic, 1 H and 13 C NMR and X-ray photoelectron spectroscopies, magnetic susceptibilities measurements, mass spectrometry and TG and DSC analysis. The stoichiometry of these complexes is Pd:L = 1:2 and coordination around the metallic cation seems to be distorted square planar, close to D 2 h . Coordination takes place through the sulphur atoms of the ligands and the carboxylic group is in a free, acidic form. Both sulphur atoms are chemically equivalent, according to the XPS results. 1 H and 13 C NMR spectra for the DL - and L -valine derivatives indicate that different complexes DD , DL and DL do not have any spectroscopic difference due to the large distance between the chiral centers. Thermal decomposition of the complexes takes place through a multi-step process, the first step being a decarboxylation, followed by a complex pyrolysis that leads to palladium oxide. The thermal stability of these complexes decreases in the order Pd(dtc- DL - val) 2 > Pd(dtc- DL -ala) 2 > Pd(dtc-gly) 2 > Pd(dtc- DL - leu) 2 . The mass spectrometric data indicate that the [S 2 CNHCH 2 COO] + ion is formed in all cases, with the final formation of [S 2 C] + for the ligands. For the complexes, however, the species [S-C-ala] + , [S-C-val] + and [S-C-leu] + are formed.

New PtS4 chromophores of dithiocarbamates derived from α-amino acids: synthesis, characterization and thermal behaviour

Abstract Complexes of Pt(II) with dithiocarbamates derived from α-amino acid (glycine, DL-alanine, DL-valine and DL -leucine) have been synthesized. The complexes have been characterized by chemical analysis, infrared, electronic, 1 H and 13 C NMR and X-ray photoelectron spectroscopies, magnetic susceptibilities measurements and TG and DSC analysis. The stoichiometry of these complexes is Pt:L= 1:2 and coordination around the metallic cation seems to be a distorted square-planar, dose to D 2 h . Coordination takes place through the sulphur atoms of the ligands and the carboxylic group is in a free, acidic form. 13 C NMR spectra indicate that all complexes are optically inactive due to the close vicinity of the chiral centers. Thermal decomposition of the complexes takes place through a multi-step process, the first step being a decarboxylation, followed by a complex pyrolysis that leads to metallic platinum. The thermal stability of these complexes decreases in the order Pt(gly dtc) 2 > Pt( DL -ala dtc) 2 > Pt( DL - val dtc) 2 > Pt( DL -leu dtc) 2 .

Chloride and ethyl ester morpholine thiourea derivatives and their Ni(II) complexes. Crystal and molecular structures of the thiourea derivative L-leucine methyl ester and its complexes with Cu(II) and Pt(II). Growth of the pathogenic fungus Botrytis cinerea.

We have synthesized a series of ligands (1, 3, 4, 6 and 7) and some of their complexes with Ni(II), Cu(II) and Pt(II) (2, 5, 8 and 9). These compounds were studied and characterized by elemental analysis, IR and UV-Vis spectra, conductivity measurements in solution, FAB+/MS, 1H and 13C NMR, ESR, etc. Compound 7 crystallized in the orthorhombic space group P2(1)2(1)2(1), with Z = 4. Unit cell parameters were as follows: a = 21.307(2) A, alpha = 90 degrees, b = 12.498(1) A, beta = 90 degrees, c = 7.7232(4) A, gamma = 90 degrees. For seven of these compounds, the antifungal activity of a major pathogen responsible for important crop damage was studied. In general, inhibition by the ligands was higher than that of the complexes. When the thiourea was linked to some diethyl groups, the compounds showed higher antifungal activity than the morpholine groups. Compound 3 achieved total inhibition (100%).

DNA interaction and cytostatic activity of the new liver organotropic complex of cisplatin with glycocholic acid: Bamet-R2

The aim of this study was to investigate the ability of the new liver organotropic complex of cisplatin with glycocholate (GC), Bamet‐R2, to interact with DNA, inhibit its replication and hence reduce tumor‐cell proliferation. Changes in the electrophoretic mobility of the open and covalently closed circular forms of the pUC18 plasmid DNA from Escherichia coli, a shift in the denaturation temperature of double‐stranded DNA, and ethidium‐bromide displacement from DNA binding, were induced by Bamet‐R2 and cisplatin, but not by GC. Neutral‐red retention was used to measure the number of living cells in culture after long‐term (72‐hr) exposure to these compounds and to evaluate the effect on cell viability after short‐term (6‐hr) exposure. Bamet‐R2 and cisplatin, but not GC, induced significant inhibition of cell growth. This effect ranged from mild to strong, depending upon the sensitivity of the different cell types as follows: cisplatin, rat hepatocytes in primary culture < rat hepatoma McA‐RH7777 cells (rH) < human colon carcinoma LS 174T cells (hCC) < mouse hepatoma Hepa 1–6 cells (mH); Bamet‐R2, rat hepatocytes < mH ≈ hCC < rH. DNA synthesis was measured by radiolabeled‐thymidine incorporation into DNA. Bamet‐R2 and cisplatin, but not GC, significantly inhibited the rate of DNA synthesis by these cells. After short‐term exposure to Bamet‐R2 or GC, no acute cell toxicity was observed, except on hCC cells. By contrast, acute toxicity was induced by cisplatin for all cell types studied. The in vivo anti‐tumoral effect was investigated in 3 different strains of mice following s.c. implantation of tumor cells (mouse sarcoma S‐180II cells in Swiss and B6 mice and hCC cells in nude mice). In all 3 models, tumor growth was inhibited by Bamet‐R2 and cisplatin to a similar degree. However, signs of toxicity (increases in blood urea concentrations and decreases in packed blood cell volume and in liver, kidney and body weight) and a reduction in survival rate were observed only during cisplatin administration. In sum, these results indicate that this bile‐acid derivative can be considered as a cytostatic drug whose potential usefulness deserves further investigation. Int. J. Cancer 78:346–352, 1998.© 1998 Wiley‐Liss, Inc.

New organotropic compounds. Synthesis, characterization and reactivity of Pt(II) and Au(III) complexes with bile acids: DNA interactions and 'in vitro' anticancer activity.

Based on the ability of bile acids to vectorialize the cytostatic activity of other agents, we have designed and synthesized a new series of platinum and gold complexes. These compounds were studied and characterized by elemental analysis, FT-IR, FAB(+)/MS, 1H, 13C and 195Pt NMR, UV-Vis spectroscopy and conductivity measurements in solution, among other techniques. Kinetic studies carried out in aqueous solution and in the presence of different NaCl concentrations: 4 mM (similar to cytoplasmic concentration), 150 mM (similar to plasmatic concentration). The effects on the electrophoretic mobility of the pUC18 plasmid, the DNA denaturation temperature, and ethidium bromide (EtBr) binding to DNA were studied. The complexes are able to inter-react with DNA to inhibit DNA synthesis and hence, to reduce cell proliferation. The complexes were evaluated for in vitro cytostatic activity against human colon adenocarcinoma, mouse hepatoma, human hepatoma, mouse leukemia, etc. The antitumor effect of some of the compounds prepared was similar to that of cisplatin. However, other compounds had lower cytostatic activity. This different behavior can be accounted for by the structure/activity relationship (SAR), although other factors, such as uptake and the different kinetic behavior in solution, may be responsible for these differences.

Synthesis and characterization of thiourea derivatives of α-aminoacids. Crystal structure of methyl L-valinate and L-leucinate derivatives

Abstract The synthesis of methyl 2-[(3,3-diethylthioureido)phenylmethylamino]-3-methylbutyrate and -4-methylpentenoate 3 have been achieved from 3-(chlorophenylmethylene)-1,1-diethylthiourea and the methyl esters of L-valine and L-leucine. From the latter, a bis -derivative 4 was also obtained as minor reaction product. Other compounds with morpholine residues and the glycine derivatives 5 have also been prepared. The X-ray diffraction showed an extended conformation for these compounds.