Acridine

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Michel De Meo - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of the mutagenic clastogenic potential of 3 6 di substituted Acridines targeted for anticancer chemotherapy
    Food and Chemical Toxicology, 2011
    Co-Authors: Carole Di Giorgio, Yohann Benchabane, Gerard Boyer, Philippe Piccerelle, Michel De Meo
    Abstract:

    The mutagenicity and clastogenicity of a series of 18 3,6-di-substituted Acridines were evaluated by the Ames test on Salmonella typhimurium TA 97a and by the micronucleus assay on Chinese Hamster Ovary cells (CHO cells), as compared to their cytotoxicity against CHO cells. Experimental results overall demonstrated that simple symmetric molecules were more mutagenic than asymmetric structures. The mutagenic properties of Acridines on strain TA97a mainly depended on molecular geometry and length, and on the nature of the substituted groups. The clastogenicity of Acridines mainly depended on molecular length and electrophilicity in mammalian cells. Structure-activity relationships indicated that cytotoxicity could be decoupled from genotoxicity by introducing several chemical groups that induced asymmetry or bulkiness in the Acridine compounds. They led to the synthesis of the promising 3-acetamido-6-(4-fluorobenzamido)Acridine, which displayed a strong cytotoxic activity and was not mutagenic.

  • photo inducible cytotoxic and clastogenic activities of 3 6 di substituted Acridines obtained by acylation of proflavine
    European Journal of Medicinal Chemistry, 2009
    Co-Authors: Yohann Benchabane, Carole Di Giorgio, Gerard Boyer, Annesophie Sabatier, Diane Allegro, Vincent Peyrot, Michel De Meo
    Abstract:

    The cytotoxicity and photo-enhanced cytotoxicity of a series of 18 3,6-di-substituted Acridines were evaluated on both tumour CHO cells and human normal keratinocytes, and compared to their corresponding clastogenicity as assessed by the micronucleus assay. Compounds 2f tert-butyl N-[(6-tert-butoxycarbonylamino)acridin-3-yl]carbamate and 2d N-[6-(pivalamino)acridin-3-yl]pivalamide displayed a specific cytotoxicity on CHO cells. These results suggested that the two derivatives could be considered as interesting candidates for anticancer chemotherapy and hypothesized that the presence of 1,1-dimethylethyl substituents was responsible for a strong nonclastogenic cytotoxicity. Compounds 2b and 2c, on the contrary, displayed a strong clastogenicity. They indicated that the presence of nonbranched aliphatic chains on positions 3 and 6 of the Acridine rings tended to induce a significant clastogenic effect. Finally, they established that most of the Acridine compounds could be photo-activated by UVA-visible rays and focussed on the significant role of light irradiation on their biological properties.

Carole Di Giorgio - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of the mutagenic clastogenic potential of 3 6 di substituted Acridines targeted for anticancer chemotherapy
    Food and Chemical Toxicology, 2011
    Co-Authors: Carole Di Giorgio, Yohann Benchabane, Gerard Boyer, Philippe Piccerelle, Michel De Meo
    Abstract:

    The mutagenicity and clastogenicity of a series of 18 3,6-di-substituted Acridines were evaluated by the Ames test on Salmonella typhimurium TA 97a and by the micronucleus assay on Chinese Hamster Ovary cells (CHO cells), as compared to their cytotoxicity against CHO cells. Experimental results overall demonstrated that simple symmetric molecules were more mutagenic than asymmetric structures. The mutagenic properties of Acridines on strain TA97a mainly depended on molecular geometry and length, and on the nature of the substituted groups. The clastogenicity of Acridines mainly depended on molecular length and electrophilicity in mammalian cells. Structure-activity relationships indicated that cytotoxicity could be decoupled from genotoxicity by introducing several chemical groups that induced asymmetry or bulkiness in the Acridine compounds. They led to the synthesis of the promising 3-acetamido-6-(4-fluorobenzamido)Acridine, which displayed a strong cytotoxic activity and was not mutagenic.

  • photo inducible cytotoxic and clastogenic activities of 3 6 di substituted Acridines obtained by acylation of proflavine
    European Journal of Medicinal Chemistry, 2009
    Co-Authors: Yohann Benchabane, Carole Di Giorgio, Gerard Boyer, Annesophie Sabatier, Diane Allegro, Vincent Peyrot, Michel De Meo
    Abstract:

    The cytotoxicity and photo-enhanced cytotoxicity of a series of 18 3,6-di-substituted Acridines were evaluated on both tumour CHO cells and human normal keratinocytes, and compared to their corresponding clastogenicity as assessed by the micronucleus assay. Compounds 2f tert-butyl N-[(6-tert-butoxycarbonylamino)acridin-3-yl]carbamate and 2d N-[6-(pivalamino)acridin-3-yl]pivalamide displayed a specific cytotoxicity on CHO cells. These results suggested that the two derivatives could be considered as interesting candidates for anticancer chemotherapy and hypothesized that the presence of 1,1-dimethylethyl substituents was responsible for a strong nonclastogenic cytotoxicity. Compounds 2b and 2c, on the contrary, displayed a strong clastogenicity. They indicated that the presence of nonbranched aliphatic chains on positions 3 and 6 of the Acridine rings tended to induce a significant clastogenic effect. Finally, they established that most of the Acridine compounds could be photo-activated by UVA-visible rays and focussed on the significant role of light irradiation on their biological properties.

  • In Vitro Activities of 7-Substituted 9-Chloro and 9-Amino-2-MethoxyAcridines and Their Bis- and Tetra-Acridine Complexes against Leishmania infantum
    Antimicrobial agents and chemotherapy, 2003
    Co-Authors: Carole Di Giorgio, Maxime Robin, Nadine Azas, M Gasquet, Muriel Costa, Pierre Timon-david, Florence Delmas, Nathalie Filloux, Laetitia Seferian, Jeanpierre Galy
    Abstract:

    9-Chloro and 9-amino-2-methoxyAcridines bearing different substituents in position 7, as well as their corresponding unsubstituted dimeric and tetrameric complexes, were investigated for in vitro antiproliferative properties against Leishmania infantum compared to toxicity towards human monocytes. The results clearly confirmed that several compounds of the 2-methoxyAcridine series, together with their corresponding dimeric and tetrameric derivatives, had strong in vitro antiparasitic properties. Antileishmanial activity was shown to depend on the nature of both 7- and 9-substituted groups in monoAcridines, while it varied according to the nature of the 9-substituted group and the length of the linker among bis- and tetra-Acridines. The effects of Acridine derivatives on DNA synthesis raised the hypothesis that DNA metabolism constituted their main target in Leishmania promastigotes; however, secondary effects on other biochemical pathways, including protein and lipid metabolism, were observed, suggesting that Acridine compounds could be considered multitarget drugs.

Palwinder Singh - One of the best experts on this subject based on the ideXlab platform.

  • Acridine derivatives: a patent review (2009 – 2010)
    Expert Opinion on Therapeutic Patents, 2011
    Co-Authors: Jatinder Kaur, Palwinder Singh
    Abstract:

    Introduction: Acridines are highly important heterocyclic compounds with immense biological significance as they act as the central core of antitumor, anti-protozoan, antiviral and multi-drug resistance modulating agents. The tricyclic aromatic structure of Acridine is primarily responsible for its intercalation with DNA by controlling its biological profile and the substitution pattern of the molecule, which leads to several other applications. Areas covered: In this review, Acridine-based functional molecules and patents of Acridine derivatives filed from 2009 to 2010 are discussed. The latest information about the medical importance of new Acridine-based molecules is also discussed (e.g., materials with sensing and electrical/thermal properties). Expert opinion: The tricyclic aromatic heterocyclic structure of Acridine has a lot of potential for biological and material utilization. The versatility of fluorescent Acridines could be further enhanced by introducing amino-acid chains or other polar substit...

  • Acridine derivatives: a patent review (2009 - 2010)
    Expert opinion on therapeutic patents, 2011
    Co-Authors: Jatinder Kaur, Palwinder Singh
    Abstract:

    Introduction: Acridines are highly important heterocyclic compounds with immense biological significance as they act as the central core of antitumor, anti-protozoan, antiviral and multi-drug resistance modulating agents. The tricyclic aromatic structure of Acridine is primarily responsible for its intercalation with DNA by controlling its biological profile and the substitution pattern of the molecule, which leads to several other applications. Areas covered: In this review, Acridine-based functional molecules and patents of Acridine derivatives filed from 2009 to 2010 are discussed. The latest information about the medical importance of new Acridine-based molecules is also discussed (e.g., materials with sensing and electrical/thermal properties). Expert opinion: The tricyclic aromatic heterocyclic structure of Acridine has a lot of potential for biological and material utilization. The versatility of fluorescent Acridines could be further enhanced by introducing amino-acid chains or other polar substit...

Ján Imrich - One of the best experts on this subject based on the ideXlab platform.

  • Binding of Glyco-Acridine Derivatives to Lysozyme Leads to Inhibition of Amyloid Fibrillization
    Biomacromolecules, 2013
    Co-Authors: Quan V. Vuong, Ján Imrich, Andrea Antosova, Katarina Siposova, Trang Truc Nguyen, Lucia Balogova, Ladislav Drajna, Mai Suan Li, Zuzana Gazova
    Abstract:

    While amyloid-related diseases are at the center of intense research efforts, no feasible cure is currently available for these diseases. The experimental and computational techniques were used to study the ability of glyco-Acridines to prevent lysozyme amyloid fibrillization in vitro. Fluorescence spectroscopy and atomic force microscopy have shown that glyco-Acridines inhibit amyloid aggregation of lysozyme; the inhibition efficiency characterized by the half-maximal inhibition concentration IC50 was affected by the structure and concentration of the derivative. We next investigated relationship between the binding affinity and the inhibitory activity of the compounds. The semiempirical quantum PM6-DH+ method provided a good correlation pointing to the importance of quantum effects on the binding of glyco-Acridine derivatives to lysozyme. The contribution of linkers may be explained by the valence bond theory. Our data provide a basis for the development of new small molecule inhibitors effective in the...

  • Structure-activity relationship of Acridine derivatives to amyloid aggregation of lysozyme
    Biochimica et Biophysica Acta, 2011
    Co-Authors: Andrea Antosova, Ján Imrich, Pavol Kristian, Mária Vilková, Beatrice Chelli, Eva Bystrenova, Katarina Siposova, Francesco Valle, Fabio Biscarini, Zuzana Gazova
    Abstract:

    Abstract Background Amyloid-related diseases (such as Alzheimer's disease or diabetes type II) are associated with self-assembly of protein into amyloid aggregates. Methods Spectroscopic and atomic force microscopy were used to determine the ability of Acridines to affect amyloid aggregation of lysozyme. Results We have studied the effect of Acridine derivatives on the amyloid aggregation of lysozyme to investigate the Acridine structure-activity relationship. The activity of the effective planar Acridines was characterized by the half-maximum depolymerization concentration DC 50 and half-maximal inhibition concentration IC 50 . For the most effective Acridine derivatives we examined their interaction with DNA and their effect on cell viability in order to investigate their eventual influence on cells. We thus identified planar Acridine derivatives with intensive anti-amyloid activity (IC 50 and DC 50 values in micromolar range), low cytotoxicity and weak ability to interfere with the processes in the cell. Conclusions Our findings indicate that both the planarity and the tautomerism of the 9-aminoAcridine core together with the reactive nucleophilic thiosemicarbazide substitution play an important role in the anti-amyloid activities of studied derivatives. General significance The present findings favor the application of the selected active planar Acridines in the treatment of amyloid-related diseases.

  • synthesis and properties of novel biologically interesting polycyclic 1 3 4 oxadiazoles containing Acridine acridone moieties
    Heterocycles, 2009
    Co-Authors: Ján Imrich, Pavol Kristian, Jana Tomascikova, Maria Kozurkova, Zdenka Frohlichova, Ivan Danihel, Stanislav Bohm, Danica Sabolova, Karel D. Klika
    Abstract:

    A series of polycyclic 1,3,4-oxadiazoles bearing Acridine and acridone pharmacophores were synthesized as potential noncovalent DNA-binding and antitumor agents. The synthesis of oxadiazoles with acridone moiety was performed exploring oxidative cyclization of corresponding aldimines via bromine and the Acridine derivatives by cyclization of acylthiosemicarbazides with mercuric oxide. The spectroscopic properties of the compounds in the case of acridonoxadiazoles showed an efficient binding activity to DNA (K = 5.3-9.2 × 10 4 M -1 ), whereas the Acridine analogues are suitable as biomarkers. The structure of compounds were characterized by spectral methods (UV-vis, IR, 1 H, 13 C, and 2D NMR) and quantum-chemical calculations (DFT, ZINDO).

  • Acridine derivatives inhibit lysozyme aggregation.
    European Biophysics Journal, 2008
    Co-Authors: Zuzana Gazova, Andrea Bellova, Zuzana Daxnerova, Ján Imrich, Pavol Kristian, Jana Tomascikova, Jaroslava Bagelova, Diana Fedunova, Marián Antalík
    Abstract:

    We have screened a library of structurally distinct Acridine derivatives (19 compounds) for their ability to inhibit lysozyme amyloid aggregation in vitro. Studied Acridines were divided into three structurally different groups depending on the molecule planarity and type of the side chain—planar Acridines, spiroAcridines and tetrahydroAcridines. Thioflavine T fluorescence assay and transmission electron microscopy were used for monitoring the inhibiting activity of Acridines. We have found that both the structure of the Acridine side chains and molecule planarity influence their antiamyloidogenic activity. The planar Acridines inhibited lysozyme aggregation effectively. SpiroAcridines and tetrahydroAcridines had no significant effect on the prevention of lysozyme fibrillization, probably resulting from the presence of the heterocyclic 5-membered ring and non-planarity of molecule. Moreover, in the presence of some tetrahydroAcridines the enhanced extent of aggregation was detected. We identified the most active Acridine derivates from studied compound library characterized by low micromolar IC50 values, which indicate their possible application for therapeutic purpose.

  • Unusual structures derived from N‐acridin‐9‐yl methyl N′‐acridin‐9‐yl thiourea based on the propensity of N‐10 to retain H
    Journal of Heterocyclic Chemistry, 2006
    Co-Authors: Karel D. Klika, Ján Imrich, Kalevi Pihlaja, Mária Vilková, Juraj Bernát
    Abstract:

    N-Acridin-9-yl methyl N′-acridin-9-yl thiourea spontaneously spiro cyclises via nucleophilic attack of the methylene carbon onto the C-9 of the other Acridine moiety. The thiourea, upon reaction with bromoacetonitrile, provided a spiro fused-bicyclic product displaying unusual dynamic behavior.

Jean-michel Chezal - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of new iodinated Acridine derivatives for targeted radionuclide therapy of melanoma using ^125I, an Auger electron emitter
    Investigational New Drugs, 2011
    Co-Authors: Maryline Gardette, Nicolas Desbois, Pierre Labarre, Ting-dee Wu, Jean-luc Guerquin-kern, Janine Papon, Jean-claude Madelmont, Elisabeth Miot-noirault, Mathilde Bonnet, Jean-michel Chezal
    Abstract:

    The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodobenzamides or analogs are known to possess specific affinity for melanoma tissue. New heteroaromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using ^125I, which emits Auger electrons and gives high-energy, localized irradiation. Two iodinated Acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with ^125I, the two compounds induced in vitro a significant radiotoxicity to B16F0 melanoma cells. Nevertheless, the Acridine compound appeared more radiotoxic than the acridone compound. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with acridone derivative, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. In conclusion, the Acridine derivative with a higher nuclear localization appeared a better candidate for application in targeted radionuclide therapy using ^125I.

  • simple and convenient conversion of acridones into 9 unsubstituted Acridines via acridanes using borane tetrahydrofuran complex
    Tetrahedron Letters, 2009
    Co-Authors: Nicolas Desbois, Aurélie Maisonial, Yves Blache, Anna Szollosi, Valerie Weber, Emmanuel Moreau, Jeanclaude Teulade, Olivier Chavignon, Jean-michel Chezal
    Abstract:

    A new method for the synthesis of 9-unsubstituted Acridines from acridones using mild conditions is described. Various Acridines bearing reduction-sensitive group(s) have been synthesized from the corresponding acridones using a two-step procedure that involved a commercially available borane complex reduction followed by an acridane oxidation.