title: Bivalent sequential binding of docetaxel to methyl-β-cyclodextrin.
abstract: New docetaxel (Dtx) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility (up to 9.98mgmL(-1)) were obtained from phase solubility diagrams. γ-CD and SBE-β-CD offered only poor solubility enhancements while considerable increases in apparent solubility were obtained with Me-β-CD (20%, w/w) and HP-β-CD (40%, w/w) (9.98mgmL(-1) and 7.43mgmL(-1), respectively). The complexation mechanism between Dtx and Me-β-CD was investigated by circular dichroism spectrometry, two-dimensional (1)H NMR (NOESY) in D(2)O, isothermal titration calorimetry (ITC) and molecular docking calculations. Circular dichroism and NOESY confirmed the existence of non-covalent interactions between Dtx and Me-β-CD and suggested that the tert-butyl group (C(6)-C(9)) and two aromatic groups (C(24)-C(29) and C(30)-C(35)) of Dtx interacted with the Me-β-CD molecules. The combination of ITC results to molecular docking calculations led to the identification of an unconventional sequential binding mechanism between Me-β-CD and Dtx. In this sequential binding, a Me-β-CD molecule first interacted with both tert-butyl and C(30)-C(35) aromatic groups (K(1): 744M(-1)). Then a second Me-β-CD molecule interacted with the C(24)-C(29) aromatic group (K(2): 202M(-1)). The entropy of the first interaction was positive, whereas a negative value of entropy was found for the second interaction. The opposite behavior observed for these two sites was explained by differences in the hydrophobic contact surface and functional group flexibility.
authors: Univ Paris-Sud, School of Pharmacy, Chatenay-Malabry, France. silvia.mazzaferro@u-psud.fr
authors: Silvia
authors: S
authors: Mazzaferro
authors: Kawthar
authors: K
authors: Bouchemal
authors: Jean-François
authors: JF
authors: Gallard
authors: Bogdan I
authors: BI
authors: Iorga
authors: Monique
authors: M
authors: Cheron
authors: Claire
authors: C
authors: Gueutin
authors: Claire
authors: C
authors: Steinmesse
authors: Gilles
authors: G
authors: Ponchel
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002942:Circular Dichroism / Q000379:methods; D003505:Cyclodextrins / Q000737:chemistry; D000077143:Docetaxel; D019277:Entropy; D008958:Models, Molecular; D015394:Molecular Structure; D012995:Solubility; D043823:Taxoids / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D003505:Cyclodextrins; D043823:Taxoids; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D000077143:Docetaxel