Preactivated oxazaphosphorines designed for isophosphoramide mustard delivery as bulk form or nanoassemblies: Synthesis and proof of concept

Charles Skarbek, Lea L. Lesueur, Hubert Chapuis, Alain Deroussent, Catherine Piochedurieu, Aurore Daville, Joachim Caron, Michael Rivard, Thierry Martens, Jean Rémi Bertrand, Eric Le Cam, Gilles Vassal, Patrick Couvreur, Didier Desmaele, Angelo Paci

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

14 Citations (Scopus)

Résumé

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.

langue originaleAnglais
Pages (de - à)705-717
Nombre de pages13
journalJournal of Medicinal Chemistry
Volume58
Numéro de publication2
Les DOIs
étatPublié - 22 janv. 2015
Modification externeOui

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