Biomedical subjects

Irena Kostova

Publications and source records attributed to Irena Kostova.

14 recordsLinked to original sources

PubMed2006

New lanthanum (III) complex--synthesis, characterization, and cytotoxic activity.

The complex of lanthanum (III) was synthesized reacting the respective inorganic salt with 5-aminoorotic acid in amounts equal to the metal:ligand molar ratio of 1:3. The complex was prepared by adding an aqueous solution of lanthanum (III) nitrate to an aqueous solution of the ligand, subsequently raising the pH of the mixture gradually to approx. 5.0 through addition of a dilute solution of sodium hydroxide. The structure of the final complex was determined by means of spectral data (IR, Raman,( 1)H-NMR) and elemental analysis. Significant differences in the IR spectrum of the complex were observed as compared to the spectrum of the ligand. A comparative analysis of the Raman spectrum of the complex with that of the free 5-aminoorotic acid allowed a straightforward assignment of the vibrations of the ligand groups involved in coordination. The ligand and the complex were tested for the cytotoxic activities on the chronic myeloid leukemia derived K-562, overexpressing the BCR-ABL fusion protein and the non-Hodgkin lymphoma derived DOHH-2, characterized by a re-expression of the anti-apoptotic protein bcl-2 cell lines. The results obtained indicate that the tested compounds exerted a considerable cytotoxic activity upon the evaluated cell lines in a concentration-dependent matter, which enabled the construction of dose-response curves and the calculation of the corresponding IC(50 )values. The inorganic salt exerted a very weak cytotoxic effect on these cells, which is in contrast to the lanthanum (III) complex.

Antineoplastic Agents↗

PubMed2006

Ruthenium complexes as anticancer agents.

Cancer is one of the major cases of death in the world. Current treatment of cancer is limited to surgery, radiotherapy, and the use of cytotoxic agents, despite their well known side effects and problems associated with the development of resistance. For most forms of disseminated cancer, however, no curative therapy is available, and the discovery and development of novel active chemotherapeutic agents is largely needed. Since the development of cisplatin, an inorganic platinum complex, numerous platinum and non-platinum metal complexes were synthesized and tested for anticancer activity. Very few match the clinical efficacy of cisplatin. Ruthenium complexes were prepared to ameliorate cisplatin activity, particularly on resistant tumours, or to reduce host toxicity at active doses. Since many years a lot of scientific groups have actively worked in the field of inorganic antitumor drugs and have developed a number of Ru(II) and Ru(III) complexes, which were shown to possess good antitumor and, above all, antimetastatic properties against animal models. Ruthenium complexes are presently an object of great attention in the field of medicinal chemistry, as antitumor agents with selective antimetastatic properties and low systemic toxicity. Ruthenium compounds appear to penetrate reasonably well the tumor cells and bind effectively to DNA. In this review, the achievements in the field of medicinal chemistry, DNA binding modes, and the development status of Ru(II) and Ru(III) complexes as anticancer agents are discussed. The aim of this review is therefore that of critically examining the past and the actual work on ruthenium compounds with emphasis on their proposed role in cancer therapy.

Animals↗

PubMed2006

Synthetic and natural coumarins as antioxidants.

Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogs. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their antioxidant effects were extensively examined. In this review, plant derived coumarins and their synthetic analogs will be systematically evaluated based on their plant origin, structure-activity relationship and antioxidant efficacy. Owing their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action has not yet been fully understood and the correlation of effects with chemical structure is not conclusive at the moment. It is the objective of this review will be to summarize experimental data for different coumarins used as antioxidant agents, because promising data have been reported for a series of these agents. In addition, their ability to bind metal ions represents an additional means of modulating their pharmacological responses.

Animals↗

PubMed2006

Coumarins as inhibitors of HIV reverse transcriptase.

Acquired immunodeficiency syndrome (AIDS), a degenerative disease of the immune and central nervous systems, is an enormous world-wide health threat. No cure has been found, and research is aimed at developing chemotherapy against the causative agent, human immunodeficiency virus (HIV). Chemotherapy for AIDS has progressed steadily in the past decade. However, new, effective, and less toxic chemotherapeutic agents are still needed. Plants, particularly anti-infective or immunomodulating herbal medicines, can serve as sources of new active leads to be further developed as anti-AIDS drug candidates. A lot of structurally different natural coumarins were found to display potent anti-HIV activity and continued progress is anticipated in the discovery of new leads and in the development of these agents as potential anti-AIDS drug candidates. Recent studies based on the account of various coumarins from plant sources and their analogs--synthetic coumarins, indicate that some of them serve as potent nonnucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The current review demonstrates the variety of coumarins of natural plant origin and synthetic coumarins having unique mechanism of action to one of the most important stage of HIV replication (RT-inhibition). The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed. The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against drug-resistant mutants.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Cerium(III) and neodymium(III) complexes as scavengers of X/XO-derived superoxide radical.

The cerium (III) and neodymium (III) complexes with 3,3'-benzylidenebis[4-hydroxycoumarin] were synthesized and characterized by different analytical and spectral methods. The synthesis of these complexes is taken into consideration with cytotoxic screening and study of their antioxidant effect. Their cytotoxicity toward cancerous cell cultures correlated with the weakness of the coordinative bond between the cation and organic ligand and with the capability to scavenge superoxide radicals as well. On the basis of the data reported by us earlier and our new results, it was proposed that cerium (III) complex with 3,3'-benzylidenebis[4-hydroxycoumarin] might induce intracellular acidification along with control over the extracellular oxidative stress.

Antioxidants↗

PubMed2006

Gold coordination complexes as anticancer agents.

Metal ions are known to bind with nucleic acids and thereby alter their conformation and biological function. The metal ion-base interaction depends on the nature of both metal and bases; a certain site of coordination is preferred. One of the most notable successes for inorganic drugs has been the effectiveness of platinum complexes against cancer. These advances have spurred a surge of investigations to identify new inorganic agents for use in chemotherapy with improved specificity and decreased toxic side effects. Gold(I) and gold(III) complexes, the last isostructural and isoelectronic with platinum(II) complexes, are potentially attractive as anticancer agents. The design of an effective anticancer agent is a complicated game that must encompass not only the drug's inherent inhibitory properties but also its delivery, dosage, and residence time in vivo. Gold(I) and gold(III) complexes overcome some of these challenges by forming strong covalent attachments to targets. Au(III) isoelectronic with Pt(I1)-d8 system usually forms square planar complexes in solution. Since the square planar geometry of Pt(II) is important for its action as an anticancer drug, Au(III) compounds also can be used for the same purpose with the added advantage of decreased toxicity. This, together with the recent finding that certain transitional metal complexes like Au and Pt complexes have been found to be potentially useful in cancer chemotherapy, created a renewed interest in the study of the interactions of metal ions with respect to the site of binding and the structure and stability of the complexes. This work was motivated by the thought that information on the variety of Au(III) complexes and their effects can be obtained by studying the properties of Au complexes with various ligands. Various studies in the past have shown that Au complexes are very attractive in view of their application as anticancer agents.

Antineoplastic Agents↗

PubMed2005

Cytotoxic activity of new cerium (III) complexes of bis-coumarins.

Complexes of cerium (III) with bis-coumarins: 3,3'-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one) and bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane were synthesized by reaction of cerium (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 cerium (III) salt to an aqueous solution of the ligand subsequently raising the pH of the mixture gradually to ca. 5.0 by adding dilute solution of sodium hydroxide. The cerium (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 cerium (III) complexes were interpreted on the basis of comparison with the spectra of the free ligands. This analysis showed that in the Ce (III) complexes the ligands coordinated to the metal ion through both deprotonated hydroxyl groups. On the basis of the nu(C=O) red shift observed, participation of the carbonyl groups in the coordination to the metal ion was also suggested. Cytotoxic screening by MTT assay was carried out. In the present study we performed comparative evaluation of the cytotoxic effects of the two newly synthesized cerium complexes against the acute myeloid leukemia derived HL-60 and the chronic myeloid leukemia (CML)-derived BV-173. In addition the cytotoxic effects of Ce (III) complex with 3,3'-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one) were evaluated on the CML-derived K-562 and LAMA-84 cells, characterized by relative low responsiveness to chemotherapy. The DNA isolated from the cytosolic fraction of BV-173 cells after 24 h treatment with the same complex (at 100 and 200 microM) demonstrated a laddering phenomenon that is indicative for apoptotic cell death.

Carbon Isotopes↗

PubMed2005

Cytotoxic activity of new lanthanum (III) complexes of bis-coumarins.

Complexes of lanthanum (III) with bis-coumarins: bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-2-yl-methane; bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-3-yl-methane and bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-4-yl-methane 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 ca. 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-, (1)H- 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 nu(C=O) red shift observed, participation of the carbonyl groups in the coordination to the metal ion was also suggested. Cytotoxic screening by MTT assay was carried out. In the present study, we performed comparative evaluation of the cytotoxic effects of the three newly synthesized lanthanum complexes against the acute myeloid leukemia derived HL-60 and the chronic myeloid leukemia (CML)-derived BV-173. In addition the cytotoxic effects of La (III) complex with bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-2-yl-methane were evaluated on the SKW-3 cells. In order to elucidate some of the mechanistic aspects of the observed cytotoxic effects we evaluated the ability of this complex to trigger programmed cell death (apoptosis by means of agarose gel electrophoretic analysis of DNA), isolated from the cytosolic fraction of treated SKW-3 cells. In addition, microscopic morphological evaluation of the treated cells was carried out in order to establish morphological features indicative for programmed cell death.

Antineoplastic Agents↗

PubMed2005

Theoretical and spectroscopic evidence for coordination ability of 3,3'-benzylidenedi-4-hydroxycoumarin. New neodymium (III) complex and its cytotoxic effect.

Theoretical and spectroscopic studies of 3,3'-benzylidenedi-4-hydroxycoumarin (bhc) have been performed. B3LYP/6-31G* calculations reproduced the experimental molecular structure of bhc and showed two O-H...O asymmetrical intramolecular hydrogen bonds with O...O distances 2.638 and 2.696 A. The calculated Fukui functions and Molecular Electrostatic Potential for bhc and its deprotonated form, bhc(2-), predicted that the most probable reactive sites for electrophilic attack and hydrogen bonds are the carbonyl oxygens, followed by the hydroxyl oxygens. The coordination ability of 3,3'-benzylidenedi-4-hydroxycoumarin has been proved in a complexation reaction with neodymium (III) ion. The new neodymium (III) complex of bhc was studied by elemental analyses, conductivity and other physical properties, mass spectra, (1)H, (13)C NMR, UV-Vis and IR spectroscopy. The data obtained are in agreement with the metal:ligand ratio of 1:1, and the formula Nd(bhc(2-))(OH)(H(2)O), where bhc(2-)=C(25)H(14)O(6)(2-). The vibrational analysis of the neodymium (III) complex, free bhc, and its monomeric building block, 4-hydroxycoumarin, showed that in the Nd(III) complex the ligand coordinates to the metal ion through both deprotonated hydroxyl groups. The participation of both carbonyl groups in coordination to the metal ion was confirmed by the significant shift of nu(C=O) to lower wavenumber. The evaluation of the cytotoxic activity of the new Nd(III) complex on SKW-3 and HL-60/Dox cells revealed, that it is a potent cytotoxic agent and should be subset further to more detailed pharmacological and toxicological study.

4-Hydroxycoumarins↗

PubMed2005

Antineoplastic activity of new lanthanide (cerium, lanthanum and neodymium) complex compounds.

Cerium (III), lanthanum (III) and neodymium (III) complexes with 3,3'-benzylidenebis[4-hydroxycoumarin] were synthesized in view of their application as cytotoxic agents. The complexes were characterized by different physicochemical methods: elemental analysis, mass spectrometry, 1H NMR, 13C NMR and IR spectroscopy. The spectra of the complexes were interpreted on the basis of comparison with the spectrum of the free ligand. The vibrational analysis showed that in the complexes the ligand coordinated to the metal ion through both deprotonated hydroxyl groups; however, participation of the carbonyl groups in the coordination to the metal ion was also suggested. The evaluation of the cytotoxic activity of the novel lanthanide complexes on HL-60 myeloid cells revealed that they are potent cytotoxic agents. The cerium complex was found to exhibit superior activity in comparison to the lanthanum and neodymium coordination compounds, the latter being the least active. Our data give us reason to conclude that the newly synthesized lanthanide complexes should be submitted to further more detailed pharmacological and toxicological evaluation.

4-Hydroxycoumarins↗

PubMed2005

Synthetic and natural coumarins as cytotoxic agents.

Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their cytotoxic effects were most extensively examined. In this review, their broad range of effects on the tumors as shown by various in vitro and in vivo experiments and clinical studies are discussed. Hence, these cytotoxic coumarins represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. In this review, plant derived coumarins and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy. Owing the their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It is the objective of this review to summarize experimental data for different coumarins, used as cytotoxic agents, because promising data have been reported for a series of these agents. Yet, the results from different coumarins with various tumor lines are contradictory in part. We therefore conclude that there is still a long way to go until we know which cytotoxic agent will clinically be suitable for what tumor entity for treatment. Their ability to bind metal ions represents an additional means of modulating their pharmacological responses.

Animals↗

PubMed2005

Lanthanides as anticancer agents.

The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metals and metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. A lot of metal-based drugs are widely used in the treatment of cancer. The clinical success of cisplatin and other platinum complexes is limited by significant side effects acquired or intrinsic resistance. Therefore, much attention has focused on designing new coordination compounds with improved pharmacological properties and a broader range of antitumor activity. Strategies for developing new anticancer agents include the incorporation of carrier groups that can target tumor cells with high specificity. Also of interest is to develop complexes that bind to DNA in a fundamentally different manner than cisplatin, in an attempt to overcome the resistance pathways that have evolved to eliminate the drug. This review focuses on recent advances in developing lanthanide anticancer agents with an emphasis on lanthanide coordination complexes. These complexes may provide a broader spectrum of antitumor activity. They were compared with classical platinum anticancer drugs. Lanthanides are also of interest because of their therapeutic radioisotopes. The dominant pharmacological applications of lanthanides are as agents in radioimmunotherapy and photodynamic therapy.

Animals↗

PubMed2004

Cytotoxic activity of new neodymium (III) complexes of bis-coumarins.

Complexes of neodymium (III) with bis-coumarins: 3,3'-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one); bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-2-yl-methane; bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-4-yl-methane; bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane were synthesized by reaction of neodymium (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 neodymium (III) salt to an aqueous solution of the ligand subsequently raising the pH of the mixture gradually to ca. 5.0 by adding dilute solution of sodium hydroxide. The neodymium (III) complexes with bis-coumarins were characterized by different physicochemical methods-elemental analysis, IR-, (1)H- and (13)C-NMR-spectroscopies and mass-spectral data. The spectral data of neodymium (III) complexes were interpreted on the basis of comparison with the spectra of the free ligands. This analysis showed that in the Nd (III) complexes the ligands coordinated to the metal ion through both deprotonated hydroxyl groups. On the basis of the nu(C=O) red shift observed, participation of the carbonyl groups in the coordination to the metal ion was also suggested. Cytotoxic screening by MTT assay was carried out. The complexes were tested on HL-60, HL-60/Dox and SKW-3 cell lines. The overall results from the preliminary screening program revealed that all of the new Nd (III) complexes reach 50% inhibition of the malignant cells proliferation and thus could be considered as biologically active. On the basis of the IC(50) values obtained compounds Nd(L(1))(OH).H(2)O and Nd(L(3))(OH).2H(2)O were found to exert superior activity in comparison to the remaining complexes.

Adult↗

PubMed2004

Stability of the complexes of some lanthanides with coumarin derivatives. II. Neodymium(III)-acenocoumarol.

A complex of neodymium(III) with 4-hydroxy-3[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one (acenocoumarol) was synthesized by mixing water solutions of neodymium(III) nitrate and the ligand (metal to ligand molar ratio of 1:3). The complex was characterized and identified by elemental analysis, conductivity, IR, 1H NMR and mass spectral data. DTA and TGA were applied to study the composition of the compound. Elemental and mass spectral analysis of the complex indicated the formation of a compound of the composition NdR3 x 6H2O, where R = C19H14NO6-) The reaction of neodymium(III) with acenocoumarol was studied in detail by the spectrophotometric method. The stepwise formation of three complexes, vis., NdR2+, NdR2+ and NdR3 was established in the pH region studied (pH 3.0-7.5). The equilibrium constants for 1:1, 1:2 and 1:3 complexes were determined to be log K1 = 6.20 +/- 0.06; log K2 = 3.46 +/- 0.07 and log K2) = 2.58 +/- 0.05, respectively.

Acenocoumarol↗