Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 94, Issue -, Pages 45-55Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.02.044
Keywords
Harmine derivatives; Antiproliferative activity; Cytostatic activity; Comparative molecular field analysis
Categories
Funding
- FNRS [7.4.529.13.F., 4525.11]
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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. (C) 2015 The Authors. Published by Elsevier Masson SAS.
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