Browsing by Author "Wesselinova D."

Now showing 1 - 5 of 5
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    COMPUTER MODELLING OF ALL TYPES OF SOMATOSTATIN RECEPTORS
    (2020-01-01) Dzimbova T.; Wesselinova D.; Naydenova E.; Milanov P.
    The somatostatin receptors (SSTRs) are a very important class of receptors that attract the attention of a great number of scientists. The development of effective and selective ligands of each somatostatin receptor type is a time consuming process, which involves the knowledge and the skills of different researchers: chemists, biologists, medics, pharmacologists, etc. A large number of compounds is synthesized, characterized and biologically tested, but just some of them have the desired efficacy and selectivity to a respective somatostatin receptor type. The aims of the present study are: (1) to choose templates, among the recently published crystallographic structures, for homology modelling of all five types of SSTRs; (2) to evaluate the models by different computational tools (Procheck, MolProbity, docking). The structures of SSTRs are modelled using the Chimera software and their characteristics are evaluated on the ground of different methods. The best models are used for docking with recently synthesized and biologically tested somatostatin analogues selective to certain SSTR. The data, especially from docking, shows that the newly generated model of SSTRs could be further used for in silico experiments providing a faster and a better design of selective and effective ligands of SSTRs
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    New C2-and N3-Modified Thieno[2,3-d]Pyrimidine Conjugates with Cytotoxicity in the Nanomolar Range
    (2022-04-01) Mavrova A.T.; Dimov S.; Yancheva D.; Rangelov M.; Wesselinova D.; Naydenova E.
    Aims: The aim of the current study was to develop and explore a series of new cytotoxic agents based on the conjugation between the thieno[2,3-d]pyrimidine moiety and a second pharmacophore at the C2 or N3 position. Background: As the thieno[2,3-d]pyrimidine core is a bioisostere of the 4-anilinoquinazoline, various new thienopyrimidine derivatives were synthesized by modifying the structure of the clinically used anticancer quinazoline EGFR inhibitors of the first generation – gefitinib, and second-generation – dacomitinib and canertinib. It was reported that some thieno[2,3-d]pyrimidine derivatives showed improved EGFR inhibitory activity. On the other hand, the benzimidazole heterocycle is present as a pharmacophore unit in the structure of many clinically used chemotherapeutic agents. Some 2-aminobenzimidazole derivatives, possessing anticancer activity, demonstrated EGFR inhibition and the benzimidazole derivative EGF816 is currently in the second phase of clinical trials. Objective: The objectives of the study were the design of a novel series thieno[2,3-d]pyrimidines, synthesis of the compounds and investigation of their effects towards human cancer HT-29, MDA-MB-231, HeLa, HepG2 and to normal human Lep3 cell lines. (American Type Culture Collection, ATCC, Rockville, MD, USA). Methods: The synthetic protocol implemented cyclocondensation of 2-amino-thiophenes and nitriles in an inert medium, azaMichael addition to benzimidazole derivatives and nucleophylic substitution at the N3 place. MTS test was used in order to establish the cytotoxicity of the tested compounds. SAR analysis and in silico assessment of the inhibitory potential towards human oncogenicV599EB-Raf were performed using Molinspiration tool and Molecular Operating environment software. Results: The MTS test data showed that almost all studied thieno[2,3-d]pyirimidines (9-13, 21-22 and 25) manifest high inhibitory effect on cell proliferation at nanomolar concentrations, whereas compounds 9 (IC50 = 130 nM) and 10 (IC50 = 261 nM) containing amino acid moiety, and 21 (IC50 = 108 nM) possessing two thienopyrimidine moieties attached to a 1,3-disubstituted benzimidazole linker, revealed many times lower toxicity against Lep3 cells compared to the cancer cells. Thienopyrimidines 11-13 possessed high selectivity against HeLa cells. Compound 13 showed high inhibitory activity against MDA-MB-231 and HepG2, with IC50 1.44 nM and 1.11 nM respectively. To outline the possible biological target of the studied coumpounds, their potential to interact with human oncogenicV599EB-Raf was explored by a docking study. As a result, it was suggested that the benzimidazolyl and glycyl fragments could enhance the binding ability of the new compounds by increasing the number of hydrogen bond acceptors and by stabilizing the inactive form of the enzyme. Conclusion: The thienopyrimidines tested in vitro for human cancer HT-29, MDA-MB-231, HeLa, HepG2 and normal human Lep3 cell lines demonstrated cytotoxicity in the nanomolar range. It was established that compounds 9, 10 and 21 showed many times lower toxicity against normal Lep3 cells that can provide a high selectivity towards all four cancer cell lines at small concentrations. Based on the analysis of the structure-activity relationship, the observed trends in the cytotoxicity could be related to the lipophilicity and the topological polar surface area of the tested compounds. The docking study on the potential of the new thieno[2,3-d]pyrimidine-4-ones to interact with mutantV599EB-Raf showed that the compounds might be able to stabilize the enzyme in its inactive form.
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    Synthesis and biological activity of novel heavy metal complexes of 5-amino-1, 10-phenanthroline and 1,10-phenanthroline
    (2012-08-01) Kaloyanov N.; Neykov M.; Wesselinova D.; Dimitrov G.
    Novel heavy metal complexes: Sr(5-NH 2-phen) 4(NO 3)(OH)(H 2O) 2 (1) (synthesized via a static self-assembly process) and Sn(phen) (NO 3)(OH)(H 2O) (2), Sn(5-NH 2-phen)(OH)(Cl)(H 2O) (3), Pb(5-NH 2-phen)(NO 3) 2(H 2O) (4) (obtained via metal competitive reactions under mild conditions) were reported. The coordination compounds were characterized by elemental analysis, FTIR-spectroscopy and FAB-mass spectrometry. Their cytotoxicity was measured by MTS-test towards human tumour (MDA-MB-231, HT-29, HeLa, HepG2) and non-tumour diploid (Lep-3) cell lines. The most pronounced cytotoxic effect on all cancer lines showed 1 and 4 at their high concentrations as well as 1 at its lower ones (≤ 4×10 -2 mg). Therefore, strontium complex of 5-amino-o-phenanthroline (1) exhibited the widest antitumour spectrum activity, having no toxicity to non-tumour cells at quantities ≤ 4×10 -2 mg. The computed EC 50 values of 1-4 against MDA-MB-231, HT-29, HeLa, HepG2 varied from 1.40×10 -3 to 6.31×10 -6 M. Towards Lep-3 substances 2-4 showed IC 50 7.52×10 -4 - 0.44 M. Substance 1 possess EC 50=1. 26×10 -7 M to the non-tumour cells. © Versita Sp. z o.o.
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    Synthesis of some novel 2-substituted-[1,3]thiazolo[3,2-a]benzimidazol-3(2h)-ones as potent cytostatic agents
    (2016-01-01) Mavrova A.; Wesselinova D.; Anichina K.
    An optimized method for the synthesis of new 2-substituted-thiazolo[2,3-a]benzimidazole-3(2H)-ones was developed which enabled the target compounds to be obtained in relative good yields through one pot process.Four cancer cell lines: human colorectal cancer cell line HT-29, breast cancer cells MDA-MB-231, cervical cancer cells HeLa, human liver carcinoma cell line HepG2 and human diploid cell line Lep-3 were used to estimate the effects of the newly synthesized compounds on cell proliferation. The initial biological screening in vitro, using MTS tetrazolium assay showed that the tested thiazolobenzimidazolones (compounds 7 and 11) demonstrated selective cytotoxicity against HT-29 cells (IC50 - 3.5.10-2 μM and IC50 - 5.0.10-2 μM, respectively), while compound 9 manifested selective cytotoxicity against Hep G2. Beside that the compounds 9 and 11 induced proliferation activity towards Lep3 cells at extremely low concentrations. EC50 values were 3.4.10-2 μM and 1.410-2 μM, correspondingly. The activity results towards HT-29 and Hep G2 cells indicated the necessity for further investigation in vivo to estimate the exact inhibition pathway of the cellular processes.
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    Synthesis, characterization and cytotoxic activity of novel Cu(II) and Co(II) complexes with 3-amino-5, 5-dimethylhydantoin
    (2014-01-01) Georgieva S.; Todorov P.; Wesselinova D.
    Novel mixed complexes of copper (II) and cobalt (II) with 3-amino-5,5-dimethylhydantoin were synthesized and their in vitro anticancer activity was investigated. The structures of the compounds were confirmed by IR, UV-Vis spectrometry, voltammetry and elemental analysis. The cytotoxic effects of novel complexes of copper (II) and cobalt (II) with 3-amino-5,5-dimethylhydantoin were tested against a panel of human tumor cell lines. All of the compounds investigated exhibited different concentration-dependent antiproliferative effects against the HT29, MDA-MB-231, HepG2 and HeLa cell lines after 24 h of treatment. The most sensitive cells were the HepG2 cells at various concentrations of both tested compounds followed by HT29.