title: Preparation and characterization of a new harmine-based antiproliferative compound in complex with cyclodextrin: Increasing solubility while maintaining biological activity.
abstract: 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 2 HP-βCD). Phase solubility experiment in presence of 2 HP-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 (1)H NMR. Secondly, (1)H 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.
authors.affiliation: Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (UNamur), 61, rue de Bruxelles, 5000 Namur, Belgium. Electronic address: celine.meinguet@unamur.be.
authors.forename: Céline
authors.initials: C
authors.lastname: Meinguet
authors.affiliation: Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (UNamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.affiliation: Namur Medicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (UNamur), 61, rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003505:Cyclodextrins / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D006247:Harmine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D012995:Solubility
chemical_list: D003505:Cyclodextrins; D006247:Harmine
keywords: Antiproliferative activity; Complexation; Cyclodextrin; Solubility