3D-QSAR, design, synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties.
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.
Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium. Electronic address: celine.meinguet@unamur.be.
Céline
C
Meinguet
Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium.
Céline
C
Bruyère
Medicinal Chemistry Research Group (CMFA), University of Louvain (UCL), 73, Avenue Mounier, 1200 Bruxelles, Belgium.
Raphaël
R
Frédérick
Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium.
Véronique
V
Mathieu
Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
Christelle
C
Vancraeynest
Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
Lionel
L
Pochet
Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
Julie
J
Laloy
Institute of Pharmacy, Freie Universität Berlin, 2+4 Königin Luise Straβe, 14195 Berlin, Germany.
Jérémie
J
Mortier
Institute of Pharmacy, Freie Universität Berlin, 2+4 Königin Luise Straβe, 14195 Berlin, Germany.
Gerhard
G
Wolber
Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium.
Robert
R
Kiss
Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
Bernard
B
Masereel
Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
Johan
J
Wouters
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006247:Harmine / Q000737:chemistry; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D016018:Least-Squares Analysis; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D006247:Harmine
Antiproliferative activity; Comparative molecular field analysis; Cytostatic activity; Harmine derivatives