title: Preactivated oxazaphosphorines designed for isophosphoramide mustard delivery as bulk form or nanoassemblies: synthesis and proof of concept.
abstract: Oxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several O- and S-alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4-hydroxy-IFO from these preactivated IFO analogues in plasma are reported.
authors.affiliation: Université Paris-Sud, Centre National de la Recherche Scientifique (CNRS), and Gustave Roussy Cancer Campus Grand Paris, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, UMR 8203 , Villejuif, France -94805.
authors.forename: Charles
authors.initials: C
authors.lastname: Skarbek
authors.forename: Lea L
authors.initials: LL
authors.lastname: Lesueur
authors.forename: Hubert
authors.initials: H
authors.lastname: Chapuis
authors.forename: Alain
authors.initials: A
authors.lastname: Deroussent
authors.forename: Catherine
authors.initials: C
authors.lastname: Pioche Durieu
authors.forename: Aurore
authors.initials: A
authors.lastname: Daville
authors.forename: Joachim
authors.initials: J
authors.lastname: Caron
authors.forename: Michael
authors.initials: M
authors.lastname: Rivard
authors.forename: Thierry
authors.initials: T
authors.lastname: Martens
authors.forename: Jean-Rémi
authors.initials: JR
authors.lastname: Bertrand
authors.forename: Eric
authors.initials: E
authors.lastname: Le Cam
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaele
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000378:metabolism; D010752:Phosphoramide Mustards / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010752:Phosphoramide Mustards; D011355:Prodrugs; C027061:isophosphamide mustard; C039771:4-hydroxyifosfamide; D007069:Ifosfamide