1 research outputs found
Preactivated Oxazaphosphorines Designed for Isophosphoramide Mustard Delivery as Bulk Form or Nanoassemblies: Synthesis and Proof of Concept
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 <i>O-</i> and <i>S-</i>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