Preparation and characterization of a new harmine-based antiproliferative compound in complex with cyclodextrin: Increasing solubility while maintaining biological activity

The trisubstituted harmine derivative, 2, present a submicromolar antiproliferative activity on 5 cancer cell lines but a moderate kinetic solubility in pH 7.4 buffer. The aim of this work was to develop a 2-cyclodextrin complex in order to increase the drug solubility while maintaining the biological activity. Firstly, the 2 increasing solubility in presence of several cyclodextrins (CDs) has been shown, with a maximum for 7 glucose subunit CD (βCD and 2HP-βCD). Phase solubility experiment in presence of 2HP-βCD has underline an AL-type profile until 80 mM which suggest a 1:1 stoichiometry and a K1:1 of 116 M−1 and a CE of 0.28 have been calculated. This 1:1 stoichiometry was confirmed by Job Plot experiment, following the CD H-3 proton by 1H NMR. Secondly, 1H NMR study of compound 2 in presence of βCD and geometry optimization of the complex has underline an inclusion of 2 into the CD, via the indole part of the drug. Finally, the efficiency of the 2 antiproliferative effect is not affected by the complexation, as shown by viability test.

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