Phthalimido-ferrocidiphenol cyclodextrin complexes: Characterization and anticancer activity

Feten Najlaoui (1, 2, 3) , Pascal Pigeon (4, 5, 6) , Zaineb Abdelkafi (7) , Sebastien Leclerc (8) , Pierrick Durand (9) , Mohamed El Ayeb (1) , Naziha Marrakchi (1) , Ali Rhouma (2) , Gérard Jaouen (4, 5, 6) , Stéphane Gibaud (3)

1 Laboratoire des Venins et Toxines, Institut Pasteur de Tunis
2 Protection des plantes cultivées et environnement
3 CITHEFOR - Cibles thérapeutiques, formulation et expertise pré-clinique du médicament
4 ENSCP - Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL
5 IPCM - Institut Parisien de Chimie Moléculaire
6 CHEMBIO - Chemical Biology
7 LR11IPT08 - Laboratoire des Venins et Biomolécules Thérapeutiques - Laboratory of Venoms and Therapeutic Biomolecules
8 LEMTA - Laboratoire d'Energétique et Mécanique Théorique et Appliquée
9 CRM2 - Cristallographie, Résonance Magnétique et Modélisations

Several ferrocenyl analogues of tamoxifen have already showed strong antiproliferative activity in experimental glioma models. Nevertheless, these compounds are very poorly soluble in water and an adapted formulation is needed. In this work, we have tailored and optimized methylated cyclodextrin soluble complexes of phthalimido-ferrocidiphenol for the first time. The complexes were characterized, and the optimized formulation was tested for in vitro efficacy and cell proliferation assays on U87, human glioblastoma cancer cells. Molecular modeling can provide accurate information about the inclusion process. The inclusion of all the moieties at the same time (i.e., ferrocene, phthalimidylpropyl, 2 phenols) is not possible due to the steric hindrance of the 1:4 system. The 1:3 systems are possible but do not seem very relevant. However, various 1:2 and 1:1 complexes are mostly present in aqueous solutions. Some experiments have confirmed our hypothesis. First, interactions between the phenol, phthalimidylpropyl and ferrocenyl groups have been observed in our NMR experiments. Second, the inclusion of phthalimidylpropyl was detected by UV-vis spectrophotometry with an apparent 1:1 interaction, which was observed through the Benesi-Hildebrand method. The complex is readily soluble in water and keeps its pharmacological activity against U87 tumor cells (IC₅₀=0.028 ± 0.007 μM vs. 0.018 ± 0.003 μM for PhtFerr).

Domains: Cancer; Organic chemistry; Pharmaceutical sciences

Feten Najlaoui, Pascal Pigeon, Zaineb Abdelkafi, Sebastien Leclerc, Pierrick Durand, et al.. Phthalimido-ferrocidiphenol cyclodextrin complexes: Characterization and anticancer activity. International Journal of Pharmaceutics, 2015, 491 (1-2), pp.323-334. ⟨10.1016/j.ijpharm.2015.06.043⟩. ⟨hal-01218567⟩