TY - JOUR
T1 - Preactivated oxazaphosphorines designed for isophosphoramide mustard delivery as bulk form or nanoassemblies
T2 - Synthesis and proof of concept
AU - Skarbek, Charles
AU - Lesueur, Lea L.
AU - Chapuis, Hubert
AU - Deroussent, Alain
AU - Piochedurieu, Catherine
AU - Daville, Aurore
AU - Caron, Joachim
AU - Rivard, Michael
AU - Martens, Thierry
AU - Bertrand, Jean Rémi
AU - Le Cam, Eric
AU - Vassal, Gilles
AU - Couvreur, Patrick
AU - Desmaele, Didier
AU - Paci, Angelo
N1 - Publisher Copyright:
© 2014 American Chemical Society.
PY - 2015/1/22
Y1 - 2015/1/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84921475048&partnerID=8YFLogxK
U2 - 10.1021/jm501224x
DO - 10.1021/jm501224x
M3 - Article
C2 - 25494842
AN - SCOPUS:84921475048
SN - 0022-2623
VL - 58
SP - 705
EP - 717
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -