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

Céline Meinguet, Céline Bruyère, Raphaël Frédérick, Véronique Mathieu, Christelle Vancraeynest, Lionel Pochet, Julie Laloy, Jérémie Mortier, Gerhard Wolber, Robert Kiss, Bernard Masereel, Johan Wouters

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.

langue originaleAnglais
Numéro d'article7726
Pages (de - à)45-55
Nombre de pages11
journalEuropean Journal of Medicinal Chemistry
Volume94
Les DOIs
étatPublié - 13 avr. 2015

    Empreinte digitale

Contient cette citation