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

@article{Skarbek2015PreactivatedOD,
  title={Preactivated oxazaphosphorines designed for isophosphoramide mustard delivery as bulk form or nanoassemblies: synthesis and proof of concept.},
  author={C. Skarbek and L. Lesueur and Hubert Chapuis and A. Deroussent and Catherine Pioche Durieu and Aurore Daville and Joachim Caron and M. Rivard and T. Martens and J. Bertrand and E. Le Cam and G. Vassal and P. Couvreur and D. Desmaele and A. Paci},
  journal={Journal of medicinal chemistry},
  year={2015},
  volume={58 2},
  pages={
          705-17
        }
}
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… Expand
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Simultaneous quantification of preactivated ifosfamide derivatives and of 4-hydroxyifosfamide by high performance liquid chromatography-tandem mass spectrometry in mouse plasma and its application to a pharmacokinetic study.
  • A. Deroussent, C. Skarbek, +7 authors A. Paci
  • Chemistry, Medicine
  • Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
  • 2015
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References

SHOWING 1-10 OF 28 REFERENCES
Design of new oxazaphosphorine anticancer drugs.
TLDR
The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists. Expand
Oxazaphosphorines: new therapeutic strategies for an old class of drugs
TLDR
An increased knowledge of oxazaphosphorines' metabolism and toxicity may allow the development of new anticancer drugs combined with drug delivery systems to circumvent drug toxicity, providing increased tumoral specificity and greater anticancer activity. Expand
New Ifosfamide Analogs Designed for Lower Associated Neurotoxicity and Nephrotoxicity with Modified Alkylating Kinetics Leading to Enhanced in Vitro Anticancer Activity
TLDR
It is hypothesized that reduced toxicogenic catabolism may induce less toxicity without changing anticancer activity, and among these new ifosfamide analogs, the 7S,9R-enantiomer will be assessed for further in vivo investigations for its antic cancer activity and its toxicological profile. Expand
Improving the antitumor activity of squalenoyl-paclitaxel conjugate nanoassemblies by manipulating the linker between paclitaxel and squalene.
TLDR
In vitro biological assessment shows that these squalenoyl-paclitaxel nanoparticles display notable cytotoxicity on several tumor cell lines including A549 lung cell line, colon cell line HT-29, or KB 3.1 nasopharyngeal epidermoid cell line and may prove useful for replacement of the toxic Cremophor EL. Expand
D-19575—a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport
TLDR
D-19575 is a new alkylating cytotoxic agent with increased antitumor selectivity, probably caused by an active transmembrane transport mechanism. Expand
Synthesis, stereochemistry and antitumor activity of 4-hydroperoxyisophosphamide (NSC-227114) and related compounds.
TLDR
The L1210 antileukemic activities revealed that the C4-hydroperoxylation of isophosphamide resulted in a marked enhancement of its activity and that the inverted stereochemistry of an alkylating functionality at the phosphorus atom is also effective in promoting the antitumor action as an alternative activated species of isphosphamide. Expand
Squalenoyl nanomedicines as potential therapeutics.
TLDR
The squalenoylation of gemcitabine and other antiretroviral nucleosides led to more potent drugs when tested in primary cultures of HIV-infected lymphocytes and in vivo in experimental leukemia both after intravenous and oral administration. Expand
Polyisoprenoyl gemcitabine conjugates self assemble as nanoparticles, useful for cancer therapy.
TLDR
Together, these findings demonstrated that the modulation of the length of nanoassemblies polyisoprenoyl moiety made tumor cells more sensitive to gemcitabine treatment without flagrant toxicity, thus providing a significant improvement in the drug therapeutic index. Expand
A unique squalenoylated and nonpegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity
TLDR
SQ-Dox nanoassembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Expand
Self-assembled squalenoylated penicillin bioconjugates: an original approach for the treatment of intracellular infections.
TLDR
It is suggested that the bioconjugation of an antibiotic to a squalene template could be a valuable approach for overcoming the antibiotic resistance due to intracellular bacterial infections. Expand
...
1
2
3
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