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

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

  • Eur J Med Chem. 2015 Apr 13:94:45-55. doi: 10.1016/j.ejmech.2015.02.044.
Céline Meinguet 1,  Céline Bruyère 2,  Raphaël Frédérick 3,  Véronique Mathieu 2,  Christelle Vancraeynest 4,  Lionel Pochet 4,  Julie Laloy 4,  Jérémie Mortier 5,  Gerhard Wolber 5,  Robert Kiss 2,  Bernard Masereel 4,  Johan Wouters 4
Affiliations

Affiliations

  • 1 Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium. Electronic address: celine.meinguet@unamur.be.
  • 2 Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium.
  • 3 Medicinal Chemistry Research Group (CMFA), University of Louvain (UCL), 73, Avenue Mounier, 1200 Bruxelles, Belgium.
  • 4 Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
  • 5 Institute of Pharmacy, Freie Universität Berlin, 2+4 Königin Luise Straβe, 14195 Berlin, Germany.
PMID: 25747498 DOI: 10.1016/j.ejmech.2015.02.044
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.

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