Irena Kostova

New lanthanide complexes of 4-methyl-7-hydroxycoumarin and their pharmacological activity.

Complexes of cerium(III), lanthanum(III) and neodymium(III) with 4-methyl-7-hydroxycoumarin (Mendiaxon, Hymecromone) were synthesized by the mixing of equimolar amounts of the respective metal nitrates and 4-methyl-7-hydroxycoumarin sodium salt in water. The complexes were characterized and identified by elemental analysis, conductivities, IR, (1)H and (13)C NMR spectroscopies and mass spectral data. DTA and TGA have been applied to study the compositions of the compounds. The newly synthesized compounds were assayed for acute intraperitoneal and per oral toxicity, influence on blood clotting time and the most active complex was investigated for spasmolytic activity. The complexes of cerium(III) and neodymium(III) showed marginal cytotoxic activity against transformed leukemic cell lines (P3HR1 and THP-1) as compared to the inorganic salts.

New metal complexes of 4-methyl-7-hydroxycoumarin sodium salt and their pharmacological activity

Complexes of copper (II), zinc (II), nickel (II), cobalt (II) and iron (III) with 4-methyl-7-hydroxycoumarin sodium salt (Mendiaxon, Hymecromone) were synthesized by mixing of equimolar amounts of the respective metal nitrates and 4-methyl-7-hydroxycoumarin sodium salt in water. The complexes were characterized and identified by elemental analysis, conductivities, IR, 1H NMR spectroscopy and mass spectral data. DTA and TGA have been applied to study the compositions of the compounds. Thermal analysis of the complexes indicate the formation of compounds which correspond to the compositions Met(HL)2 x nH2O, where Met = Cu, Zn, Ni, Co; n = 2, 3 or 4 and Fe(HL)3 x 5H2O. The newly synthesized compounds were assayed for acute intraperitoneal and per oral toxicity, influence on blood clotting time and the most active complex was investigated for spasmolytic activity.

Synthesis, physicochemical characterisation and cytotoxic screening of new complexes of cerium, lanthanum and neodymium with Warfarin and Coumachlor sodium salts

The complexes of the types Ln(HW)3•nH2O and Ln(HC)3•nH2O [where Ln = Ce, La, Nd; HW = Warfarin; HC = Coumachlor] have been synthesized by reaction of Warfarin Sodium, resp. Coumachlor Sodium and the appropriate lanthanide nitrates in various stoichiometric ratios. The formation of the complexes have been proved on the basis of elemental analysis, conductivities, IR spectroscopy and 1H-NMR spectroscopy. It is concluded that the lacton- and the keto-carbonyl groups of the ligands are bonded to the metal ion as bidentate ligand. The conductivity measurements show non-electrolytic nature of the complexes. Cytotoxicity determination by MTT-assay shows that the inorganic salts and the complexes with Warfarin did not show any significant activity. The complexes with Coumachlor were found to be more cytotoxic. The most active compound was the complex of Cerium with Coumachlor. All tested complexes showed similar in vitro cytotoxic profiles. This fact is in agreement with the formation of the complexes.

Synthesis, Physicochemical Characterization, and Cytotoxic Screening of New Zirconium Complexes with Coumarin Derivatives

Zirconium complexes of mendiaxon, warfarin, coumachlor, and niffcoumar have been synthesized by reaction of the ligands with zirconium chloride in stoichiometric ratio 1:2. The formation of the complexes has been proved on the basis of elemental analysis, IR‐spectroscopy, 1H‐NMR spectroscopy, and thermal studies. Differential thermal analyses and thermogravimetric analyses have been applied to study the compositions of the new complexes. It is concluded that the lactone‐ and the keto‐carbonyl groups of warfarin, coumachlor, and niffcoumar are bonded to the metal ion as bidentate ligands, but mendiaxon is bonded as monodentate ligand. Cytotoxic screening by MTT‐assay was carried out. Among these compounds the zirconium complex of mendiaxon showed highest cytotoxic activity against human promyelocytic leukemic HL‐60 cells. The inorganic salt was found to be active against this cell line.

Cytotoxic activity of cerium complexes with coumarin derivatives. Molecular modeling of the ligands

Cerium complexes of Umbellipherone, Mendiaxon, Warfarin, Coumachlor, and Niffcoumar have been synthesized by reaction of the ligands with cerium nitrate in a stoichiometric ratio of 1:2. The formation of the complexes has been proved on the basis of elemental analysis, conductivities, IR spectroscopy, and 1H‐NMR spectroscopy. The molecules of the ligands were optimized by means of the semiempirical quantum mechanical method PM3 to the energetically most stable conformers. All the ligands were characterized by molecular and submolecular electronic indices and the putative donor centers are proposed. It is concluded that the lactone‐ and the keto‐carbonyl groups of Warfarin, Coumachlor, and Niffcoumar are bonded to the metal ion as bidentate ligands. The other two coumarins are bonded as monodentate ligands. Conductivity measurements show the non‐electrolytic nature of the complexes. Cytotoxic screening by MTT assay was carried out. The cerium complexes were found to be more active than the inorganic salts.

Synthesis, physicochemical characterization and cytotoxic screening of new complexes of cerium, lanthanum and neodymium with Niffcoumar sodium salt

Abstract The complexes of the types Ln(HN)3.nH2O [where Ln = Ce, La, Nd; HN = Niffcoumar] have been synthesized by reaction of Niffcoumar sodium salt and the appropriate lanthanide nitrates. The solid complexes have been characterized and identified on the basis of elemental analysis, conductivities, IR- and 1H-NMR-spectroscopy. We suppose that the lacton- and keto-carbonyl oxygen atoms of Niffcoumar are bonded to the metal ion probably as a bidentate ligand. The experimental data obtained by MTT-assay show that all tested compounds manifest a similar low cytotoxic activity on lymphoma derived P3HR1 cells (20% maximum cell growth inhibition). The complexes of La and Nd have been shown to be more cytotoxic than the Ce complex against K-562 cells (about 75% maximal growth inhibition). Low to moderate cytotoxic activity has been established for the complexes of La and Ce on TPH-1 cells (25% maximum inhibition of cell growth). Our data indicate that the lanthanide complexes may have some antitumour potential which depends on the metal and the cell line used.

New Samarium(III), Gadolinium(III), and Dysprosium(III) Complexes of Coumarin-3-Carboxylic Acid as Antiproliferative Agents

New complexes of samarium(III), gadolinium(III), and dysprosium(III) with coumarin-3-carboxylic acid (HCCA) were prepared by the reaction of the ligand with respective metal nitrates in ethanol. The structures of the final complexes were determined by means of physicochemical data, elemental analysis, IR and Raman spectra. The metal-ligand binding mode in the new Ln(III) complexes of coumarin-3-carboxylic acid was elucidated. The vibrational study gave evidence for bidentate coordination of CCA− to Ln(III) ions through the carbonylic oxygen and the carboxylic oxygen atoms. The complexes were tested for antiproliferative activitiy on the chronic myeloid leukemia-derived K-562, overexpressing the BCR-ABL fusion protein. Cytotoxicity towards tumor cells was determined for a broad concentration range. The samarium salt exerted a very weak antiproliferative effect on these cells. This is in contrast to the lanthanide complexes, especially samarium complex, which exhibited potent antiproliferative activity. The present study confirms our previous observations that the lanthanide complexes of coumarins exhibit antiproliferative activity towards K-562 cell line.

Synthesis, characterization, and cytotoxic activity of new lanthanum(III) complexes of bis-coumarins.

Complexes of lanthanum(III) with bis-coumarins: 3,3′-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one) (H2L1) and bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane (H2L2) were synthesized by reaction of lanthanum(III) salt and the ligands, in amounts equal to metal : ligand molar ratio of 1 : 2. The complexes were prepared by adding an aqueous solution of lanthanum(III) salt to an aqueous solution of the ligand subsequently raising the pH of the mixture gradually to circa 5.0 by adding dilute solution of sodium hydroxide. The lanthanum(III) complexes with bis-coumarins were characterized by different physicochemical methods—elemental analysis, IR-, 1H-, and 13C-NMR-spectroscopies, and mass spectral data. The spectral data of lanthanum(III) complexes were interpreted on the basis of comparison with the spectra of the free ligands. This analysis showed that in the La(III) complexes, the ligands coordinated to the metal ion through both deprotonated hydroxyl groups. On the basis of the ν(C=O) red shift observed, participation of the carbonyl groups in the coordination with the metal ion was also suggested. In the present study, we performed a cytotoxic-effects screening of the lanthanum complexes with H2L1 and H2L2 in a panel of human tumor cell lines, using the standard MTT-dye reduction assay for cell viability. The panel consisted of the acute myeloid leukemia-derived HL-60 and the chronic myeloid leukemia-derived BV-173. Following a 24- hour treatment of BV-173 cells with lanthanum complex of H2L1 at 100 or 200 μM led to a DNA-laddering. The findings suggest that the observed cytotoxicity of the lanthanum complex of H2L1 on BV-173 is at least partly mediated through induction of programmed cell death.

Synthesis, characterization and cytotoxic/cytostatic activity of La(III) and Dy(III) complexes

New La(III) and Dy(III) complexes of deprotonated 4-hydroxy-3[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one (Acenocoumarol) were synthesized and characterized using FT-IR, FT-Raman, (1)H NMR spectra, and elemental analyses. The ligand and its lanthanide(III) complexes were tested for their cytotoxic/cytostatic activity against two tumor cell lines and peritoneal mouse macrophages. The La(III) and Dy(III) complexes exhibit good activity against melanoma B16 and fibrosarcoma L929 and they are stronger inhibitors of tumor cell proliferation compared to the ligand without influencing normal cell viability and NO release by mouse peritoneal macrophages.

Synthesis, characterization and cytotoxic/cytostatic activity of Sm(III) and Gd(III) complexes

New Sm(III) and Gd(III) complexes of deprotonated 4-hydroxy-3[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one (Acenocoumarol) were synthesized and characterized using FT-IR, FT-Raman, NMR spectra, and elemental analyses. The vibrational study gave evidence for the coordination of ligand to lanthanide ions. The ligand and its lanthanide(III) complexes were tested for their cytotoxic/cytostatic activity against two tumor cell lines and peritoneal mouse macrophages. The Sm(III) and Gd(III) complexes exhibit good activity against melanoma B16 and fibrosarcoma L929 and are stronger inhibitors of tumor cell proliferation than the ligand. Besides their cytotoxicity to tumor cells, Acenocoumarol and its gadolinium(III) and samarium(III) complexes modulate NO generation in activated macrophages.