Harmine is a natural β-carboline compound, which can be isolated from Peganum Harmala, presenting antiproliferative activity. Trisubstituted harmine derivatives were shown to be more potent than mono- and di-substituted ones [1, 2]. Here, new trisubstituted harmine derivatives were designed and synthetized in our group with the aim to overcome the intrinsic resistance of cancer cells to apoptotic stimuli.
The last step of synthesis is performed by mechanosynthesis and compounds involved in this synthesis are characterized by single-crystal X-ray diffraction. However, trisubstituted harmine derivatives often present a moderate solubility at pH 7.4. In this context cyclodextrin complexes were already prepared in our group to improve compounds solubility . Here we propose a new approach to reach this objective. Indeed, the third substituent chosen to be placed on the harmine core contains a pyridine moiety in order to improve compound solubility in comparison with benzyl moiety. Moreover, pyridine increases the tendency towards cocrystal/salt formation. This is also considered as a potential method to modulate the solubility of the compound . The aim of this work is to obtain novel druggable harmine-based molecules combining antiproliferative activity in micromolar to submicromolar range and a high solubility at physiological pH in order to allow intravenous injection of these compounds.
L.B. thanks the Fonds National pour la Recherche Scientifique-FNRS for her grant and the PC2 technological platform of UNamur.