3D-QSAR, design, synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

Apolar trisubstituted derivatives of harmine show high antiproliferative activity on diverse cancer cell lines. However, these molecules present a poor solubility making these compounds poorly bioavailable. Here, new compounds were synthesized in order to improve solubility while retaining antiproliferative activity. First, polar substituents have shown a higher solubility but a loss of antiproliferative activity. Second, a Comparative Molecular Field Analysis (CoMFA) model was developed, guiding the design and synthesis of eight new compounds. Characterization has underlined the in vitro antiproliferative character of these compounds on five cancerous cell lines, combining with a high solubility at physiological pH, making these molecules druggable. Moreover, targeting glioma treatment, human intestinal absorption and blood brain penetration have been calculated, showing high absorption and penetration properties.

langueAnglais
Numéro d'article7726
Pages45-55
Nombre de pages11
journalEuropean Journal of Medicinal Chemistry
Volume94
Les DOIs
étatPublié - 13 avr. 2015

Empreinte digitale

Harmine
Quantitative Structure-Activity Relationship
Solubility
In Vitro Techniques
Derivatives
Cell Line
Cells
Molecules
Intestinal Absorption
Glioma
Brain
Neoplasms
Blood

mots-clés

    Citer ceci

    @article{34d2c73c67b24168a04827bf91748ea2,
    title = "3D-QSAR, design, synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties",
    abstract = "Apolar trisubstituted derivatives of harmine show high antiproliferative activity on diverse cancer cell lines. However, these molecules present a poor solubility making these compounds poorly bioavailable. Here, new compounds were synthesized in order to improve solubility while retaining antiproliferative activity. First, polar substituents have shown a higher solubility but a loss of antiproliferative activity. Second, a Comparative Molecular Field Analysis (CoMFA) model was developed, guiding the design and synthesis of eight new compounds. Characterization has underlined the in vitro antiproliferative character of these compounds on five cancerous cell lines, combining with a high solubility at physiological pH, making these molecules druggable. Moreover, targeting glioma treatment, human intestinal absorption and blood brain penetration have been calculated, showing high absorption and penetration properties.",
    keywords = "Antiproliferative activity, Comparative molecular field analysis, Cytostatic activity, Harmine derivatives",
    author = "C\{'e}line Meinguet and C\{'e}line Bruy\{`e}re and Rapha\{"e}l Fr\{'e}d\{'e}rick and V\{'e}ronique Mathieu and Christelle Vancraeynest and Lionel Pochet and Julie Laloy and J\{'e}r\{'e}mie Mortier and Gerhard Wolber and Robert Kiss and Bernard Masereel and Johan Wouters",
    note = "Copyright \{circledC} 2015 The Authors. Published by Elsevier Masson SAS.. All rights reserved.",
    year = "2015",
    month = "4",
    day = "13",
    doi = "10.1016/j.ejmech.2015.02.044",
    language = "English",
    volume = "94",
    pages = "45--55",
    journal = "European Journal of Medicinal Chemistry",
    issn = "0223-5234",
    publisher = "Elsevier Masson SAS",

    }

    TY - JOUR

    T1 - 3D-QSAR, design, synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties

    AU - Meinguet,Céline

    AU - Bruyère,Céline

    AU - Frédérick,Raphaël

    AU - Mathieu,Véronique

    AU - Vancraeynest,Christelle

    AU - Pochet,Lionel

    AU - Laloy,Julie

    AU - Mortier,Jérémie

    AU - Wolber,Gerhard

    AU - Kiss,Robert

    AU - Masereel,Bernard

    AU - Wouters,Johan

    N1 - Copyright © 2015 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

    PY - 2015/4/13

    Y1 - 2015/4/13

    N2 - Apolar trisubstituted derivatives of harmine show high antiproliferative activity on diverse cancer cell lines. However, these molecules present a poor solubility making these compounds poorly bioavailable. Here, new compounds were synthesized in order to improve solubility while retaining antiproliferative activity. First, polar substituents have shown a higher solubility but a loss of antiproliferative activity. Second, a Comparative Molecular Field Analysis (CoMFA) model was developed, guiding the design and synthesis of eight new compounds. Characterization has underlined the in vitro antiproliferative character of these compounds on five cancerous cell lines, combining with a high solubility at physiological pH, making these molecules druggable. Moreover, targeting glioma treatment, human intestinal absorption and blood brain penetration have been calculated, showing high absorption and penetration properties.

    AB - Apolar trisubstituted derivatives of harmine show high antiproliferative activity on diverse cancer cell lines. However, these molecules present a poor solubility making these compounds poorly bioavailable. Here, new compounds were synthesized in order to improve solubility while retaining antiproliferative activity. First, polar substituents have shown a higher solubility but a loss of antiproliferative activity. Second, a Comparative Molecular Field Analysis (CoMFA) model was developed, guiding the design and synthesis of eight new compounds. Characterization has underlined the in vitro antiproliferative character of these compounds on five cancerous cell lines, combining with a high solubility at physiological pH, making these molecules druggable. Moreover, targeting glioma treatment, human intestinal absorption and blood brain penetration have been calculated, showing high absorption and penetration properties.

    KW - Antiproliferative activity

    KW - Comparative molecular field analysis

    KW - Cytostatic activity

    KW - Harmine derivatives

    UR - http://www.scopus.com/inward/record.url?scp=84983070540&partnerID=8YFLogxK

    U2 - 10.1016/j.ejmech.2015.02.044

    DO - 10.1016/j.ejmech.2015.02.044

    M3 - Article

    VL - 94

    SP - 45

    EP - 55

    JO - European Journal of Medicinal Chemistry

    T2 - European Journal of Medicinal Chemistry

    JF - European Journal of Medicinal Chemistry

    SN - 0223-5234

    M1 - 7726

    ER -