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

Autor: Meinguet C; Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium. Electronic address: celine.meinguet@unamur.be., Bruyère C; Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium., Frédérick R; Medicinal Chemistry Research Group (CMFA), University of Louvain (UCL), 73, Avenue Mounier, 1200 Bruxelles, Belgium., Mathieu V; Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium., Vancraeynest C; Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium., Pochet L; Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium., Laloy J; Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium., Mortier J; Institute of Pharmacy, Freie Universität Berlin, 2+4 Königin Luise Straβe, 14195 Berlin, Germany., Wolber G; Institute of Pharmacy, Freie Universität Berlin, 2+4 Königin Luise Straβe, 14195 Berlin, Germany., Kiss R; Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium., Masereel B; Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium., Wouters J; Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (Unamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2015 Apr 13; Vol. 94, pp. 45-55. Date of Electronic Publication: 2015 Feb 24.
DOI: 10.1016/j.ejmech.2015.02.044
Abstrakt: 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.
(Copyright © 2015 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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