title: Phthalimido-ferrocidiphenol cyclodextrin complexes: Characterization and anticancer activity.
abstract: 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).
authors.affiliation: Institut Pasteur de Tunis, Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, 13, Place Pasteur, 1002 Tunis, Tunisia; Olive Tree Institute, Research Unit of Plant Protection and Environment, Mahrajene City BP 208, 1082 Tunis, Tunisia; Université de Lorraine, EA 3452/CITHEFOR, 5 rue Albert Lebrun (Faculté de Pharmacie), F-54000 Nancy, France.
authors.forename: Feten
authors.initials: F
authors.lastname: Najlaoui
authors.affiliation: Chimie ParisTech, 11 rue Pierre et Marie Curie, Paris F-75231 Paris Cedex 05, France; Sorbonne Universités, UPMC Université Paris 6, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 Place Jussieu, 75252 Paris Cedex 05, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigeon
authors.affiliation: Institut Pasteur de Tunis, Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, 13, Place Pasteur, 1002 Tunis, Tunisia.
authors.forename: Zaineb
authors.initials: Z
authors.lastname: Abdelkafi
authors.affiliation: Université de Lorraine, LEMTA, UMR 7563, Faculté des Sciences et Technologies, Boulevard des Aiguillettes, Vandœuvre-lès-Nancy F-54500, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Leclerc
authors.affiliation: Université de Lorraine/CNRS, CRM2, UMR 7036, Faculté des Sciences et Technologies, Boulevard des Aiguillettes, Vandœuvre-lès-Nancy F-54500, France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Durand
authors.affiliation: Institut Pasteur de Tunis, Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, 13, Place Pasteur, 1002 Tunis, Tunisia.
authors.forename: Mohamed El
authors.initials: ME
authors.lastname: Ayeb
authors.affiliation: Institut Pasteur de Tunis, Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, 13, Place Pasteur, 1002 Tunis, Tunisia.
authors.forename: Naziha
authors.initials: N
authors.lastname: Marrakchi
authors.affiliation: Olive Tree Institute, Research Unit of Plant Protection and Environment, Mahrajene City BP 208, 1082 Tunis, Tunisia.
authors.forename: Ali
authors.initials: A
authors.lastname: Rhouma
authors.affiliation: Chimie ParisTech, 11 rue Pierre et Marie Curie, Paris F-75231 Paris Cedex 05, France; Sorbonne Universités, UPMC Université Paris 6, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 Place Jussieu, 75252 Paris Cedex 05, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
authors.affiliation: Université de Lorraine, EA 3452/CITHEFOR, 5 rue Albert Lebrun (Faculté de Pharmacie), F-54000 Nancy, France. Electronic address: stephane.gibaud@univ-lorraine.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gibaud
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005296:Ferrous Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008745:Methylation; D008958:Models, Molecular; D010797:Phthalimides / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D003505:Cyclodextrins; D005296:Ferrous Compounds; D010797:Phthalimides
keywords: Anticancer drug; Cyclodextrin; Ferrocene; Glioma; Organometallic