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Papers by Vesselina Gadjeva

Nitrosourea 1-ethyl-1-nitroso-3-[4-2,2,6,6-tetramethylpiperidine-1-oxyl (SLENU) is a spin labeled... more Nitrosourea 1-ethyl-1-nitroso-3-[4-2,2,6,6-tetramethylpiperidine-1-oxyl (SLENU) is a spin labeled analogue of the clinically used non-labeled antitumor drug lomustine (CCNU). The objective of this study is to characterize the interactions of SLENU with supported lipid films and erythrocyte membranes. Thin lipid films prepared on the surface of a glassy carbon electrode are used as a model membrane system for studying the interaction between SLENU and the lipid fraction of biomembranes. The effects of SLENU on the structure of the lipid film are investigated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). It is shown that due to the amphiphilic properties of SLENU it penetrates the lipid layers. The possible formation of defects in the lipid films was studied by the aid of hydrophilic ions-the electroactive couple ferri-ferrocyanide. The SLENU penetration in the lipid phase provokes a little decrease in the film thickness. Up to concentration of 1 mM SLEN...

Folia medica, 2008

Adverse drug reactions represent a major source of morbidity in hospitalized- and outpatients. Ad... more Adverse drug reactions represent a major source of morbidity in hospitalized- and outpatients. Adverse drug reactions may affect the function of any organ or system. Due to their clinical nonspecificity adverse drug reactions are often difficult to be recognized. The clinical manifestation, the type and severity of adverse drug reactions vary a great deal depending on patient- and drug-related factors. In recent years growing evidence has emerged implicating involvement of free radicals and reactive oxygen species in chronic degenerative diseases and in acute conditions, such as stroke and infection. The review focuses on the role of reactive oxygen species in the pathogenesis of drug-induced disease with special reference to hepatotoxicity, nephrotoxicity and allergic disease. The participation of reactive oxygen species in the development of adverse drug reactions induced by special drug classes (non-steroidal anti-inflammatory drugs, anti-infective agents, cytostatics) is describ...

Anti-cancer drug design

A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-c... more A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), using ethyl nitrite for nitrosation of the intermediate spin-labeled ureas has been described. In vitro synergistic effects of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (3b) on the cytotoxicity of bleomycin and farmorubicin were found in human lymphoid leukemia tumor cells. We measured the tissue distribution of 3b in organ homogenates of C57BL mice by an electron paramagnetic resonance method. The spin-labeled nitrosourea was mainly localized in the lungs. Our results strongly support the development and validation of a new approach for synthesis of less toxic nitrosourea derivatives as potential synergists of antitumor drugs.

Superoxide scavenging activity (SSA) of recently synthesized isonicotinoylhydrazones, analogs of ... more Superoxide scavenging activity (SSA) of recently synthesized isonicotinoylhydrazones, analogs of the clinically used anti-tuberculosis drug isoniazid (INH), was investigated using xanthine/xanthine oxidase system to generate the superoxide anion. The isonicotinoylhydrazones exhibited well expressed SSA, whereas INH did not show any SSA. All of the isonicotinoylhydrazones had a tuberculostatic activity when tested with the standard strain of Mycobacterium tuberculosis H(37)R(v) and some of them had a higher tuberculostatic activity than INH. A lower acute toxicity was also observed compared to INH. Moreover, a correlation was observed between LD(50) and SSA for the isonicotinoylhydrazones studied. An explanation is suggested for the higher tuberculostatic activity and lower acute toxicity of some of the isonicotinoylhydrazones as compared to that of INH. A new route to less toxic derivatives of INH with potential tuberculostatic activity is proposed.

International Journal of Pharmaceutics, 2001

Physicochemical properties, such as half life time (tau0.5), alkylating and carbamoylating activi... more Physicochemical properties, such as half life time (tau0.5), alkylating and carbamoylating activity and in vivo antimelanomic effects against B16 melanoma of spin labeled (containing nitroxyl free radical moiety) amino acid nitrosoureas, synthesized in our laboratory, have been studied and compared to those of the antitumor drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). We have shown that the introduction of amino acid moieties and the replacement of cyclohexylamine with nitroxyl moiety leads to a faster decomposition, higher alkylating, lower carbamoylating activity, better antimelanomic activity and lower general toxicity, when compared to those of CCNU. It was also established that spin labeled triazenes, previously synthesized by us, were more stable in phosphate saline than their nonlabeled analogue, 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (dacarbazine, DTIC). A higher cytotoxicity to B16 melanoma cells than to YAC-1 and lymphocytes was demonstrated for all spin labeled triazenes, in comparison with DTIC. An assumption has been made to explain the lower general toxicity of the spin labeled nitrosoureas compared to that of CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea and triazene derivatives as potential antimelanomic drugs might be developed.

International Journal of Pharmaceutics, 2002

Biochemical and biological activities of two recently synthesized spin labeled triazenes, contain... more Biochemical and biological activities of two recently synthesized spin labeled triazenes, containing the nitroxyl free radical moiety at different places of the triazene structure have been studied and compared with those of the antitumor drug Dacarbazine (DTIC). Tissue distribution of the triazenes was investigated in vitro in organ homogenates, tumor (B16 melanoma) and blood of C57BL mice using the electron paramagnetic resonance (EPR) method. The spin labeled triazenes were mainly localized in the tumor and in the brain. Normal leucocites, YAC-1 mNK target Moloney lymphoma cells and B16 melanoma cells were treated with spin labeled triazenes in vitro and the effects on cell viability were compared. Spin labeled 3,3-dimethyl triazene with nitroxyl radical as a substituent in the benzen ring was more cytotoxic to B16 melanoma cells than to YAC-1 Moloney lymphoma cells and normal leucocites in comparison to the spin labeled monomethyl triazene. The spin labeled derivatives were assessed with low toxicity for BDF1 mice hybrids in vivo. These results could be interpreted in terms of a possible correlation between tissue distribution and the selective antimelanoma activity of the spin labeled triazenes.

Bioorganic & Medicinal Chemistry Letters, 1998

A series of cis-restricted combretastatin analogues with 5-membered heterocycles were synthesized... more A series of cis-restricted combretastatin analogues with 5-membered heterocycles were synthesized and their inhibitory activity against microtubule assembly and cytotoxic activity against the colon 26 adenocarcinoma cancer cell line were evaluated. Some of the heterocyclic analogues showed potent antitubulin activity and cytotoxicity. Compounds 16 and 35 showed marked tumor growth suppression in the colon 26 murine tumor model.

Archives of Physiology and Biochemistry, 2001

Background: Warts are benign conditions of the skin and mucosa caused by human papilloma viruses ... more Background: Warts are benign conditions of the skin and mucosa caused by human papilloma viruses (HPV) that affect many people worlwide Objective: The aim of this study was to evaluate OS by TOS/TAS, levels of 8-hydroxy-2deoxyguanosine (8-OHdG) an indicator of DNA damage, and also protein oxidation levels by determining the dynamic serum thiol/disulfide homeostasis in patients with warts. We also aimed to investigate whether there is a relationship between thiol/disulfide homeostasis, recalcitrance of warts and DNA damage. Methods: Forty patients of age ≥ 18 years, having recalcitrant genital and/or non-genital warts that persisted for more than two years, 40 patients with warts that persisted for less than 2 years and 40 healthy controls were enrolled in the study. Blood TAS, TOS, OSI, 8-OHdG and dynamic thiol/disulfide homeostasis were evaluated. Results: Significant differences were detected between the groups in the levels of 8-OHdG, TOS, OSI, total thiol, native thiol, reduced thiol, as well as native thiol/total thiol ratio, disulfide/total thiol ratio and disulfide/native thiol ratio. Compared to the controls, patients with recalcitrant warts had significantly higher levels of 8-OHdG, TOS, and OSI levels. Total thiol and native thiol levels were significantly lower in patients with recalcitrant warts compared to patients with warts that persisted for less than 2 years. Disulfide levels were significantly higher in the latter group of patients compared to patients with recalcitrant warts and controls. Native thiol/total thiol ratio was significantly higher in both patient groups compared to controls whereas disulfide/total thiol and disulfide/native thiol ratios were significantly lower in both patient groups than in controls.

Acta Crystallographica Section D Biological Crystallography, 1995

Sulfotransferases (STs) catalyse the transfer of a sulfonyl group ('sulfation') from the enzyme c... more Sulfotransferases (STs) catalyse the transfer of a sulfonyl group ('sulfation') from the enzyme co-factor 3 0phosphoadenosine 5 0-phosphosulfate (PAPS) to a variety of biomolecules. Tyrosine sulfation of proteins and carbohydrate sulfation play a crucial role in many protein-protein interactions and cell signalling pathways in the extracellular matrix. This is catalysed by several membrane-bound STs, including tyrosylprotein sulfotransferase 1 (TPST1) and heparan sulfate 2-O-sulfotransferase (HS2ST1). Recently, involvement of these enzymes and their post-translational modifications in a growing number of disease areas has been reported, including inflammation, cancer and Alzheimer's disease. Despite their growing importance, the development of small molecules to probe the biological effect of TPST and carbohydrate ST inhibition remains in its infancy. We have used a structure-based approach and molecular docking to design a library of adenosine 3 0 ,5 0-diphosphate (PAP) and PAPS mimetics based upon 2 0-deoxyadenosine and using 2 0-deoxy-PAP as a benchmark. The use of allyl groups as masked methyl esters was exploited in the synthesis of PAP-mimetics, and click chemistry was employed for the divergent synthesis of a series of PAPS-mimetics. A suite of in vitro assays employing TPST1 and HS2ST, and a kinase counter screen, were used to evaluate inhibitory parameters and relative specificity for the STs.

Toxicology Letters, 2003

We have studied the toxic effect of the alkylating antitumor drug N ?-cyclohexyl-N-(2-chloroethyl... more We have studied the toxic effect of the alkylating antitumor drug N ?-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU) on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) strains, alone and in presence of oxygen radical-scavenging substances [Vitamin E, stable nitroxyl radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TMPO), and spin labeled (nitroxyl free radical moiety containing) analogues of CCNU] and compared with that of the alkylating antitumor drug 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (dacarbazine, DTIC). All spin labeled compounds tested were almost no toxic at doses of 50 Á/500 mM/ml, whereas the alkylating antitumor drug CCNU showed toxicity in a dose dependent manner. Even low doses of spin labeled nitrosoureas provided protection against the toxicity caused by the antitumor drug CCNU alone. The lowest toxicity against E. coli and S. aureus were achieved when 500 mM/ml of CCNU was combined with 200 mM/ml of spin labeled nitrosourea N-[N?-(2-chloroethyl)-N ?-nitrosocarbamoyl]-glycine amid of 2,2,6,6-tetramethyl-4-aminopiperidine-1-oxyl (SLCNUgly). A combination of TMPO with vitamin E completely abolished the toxicity of CCNU. Endogenous formation of oxygen radicals and their possible involvement in CCNU toxicity towards the bacteria strains tested have been also discussed.