- COMPLEXES OF 4-HYDROPEROXY IFOSFAMIDE AS ANTI-TUMOR AGENTS
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The present disclosure concerns complexes of 4-hydroperoxy ifosfamide. In one embodiment the complexes can be represented by the formula (A); wherein A represents an ammonium species selected from the conjugate acid of a basic amino acid, quaternary ammonium, aliphatic ammonium, heterocyclic ammonium, aromatic ammonium, substituted and unsubstituted pyridinium, guanidinium, and amidinium, and wherein X and Y independently represent leaving groups. Also disclosed herein are methods for making such compounds and formulating pharmaceutical compositions thereof. Methods for administering the disclosed compounds to subjects, particularly to treat hyperproliferative disorders, also are disclosed.
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Page/Page column 22-23
(2010/09/17)
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- Direct detection of the intracellular formation of carboxyphosphamides using nuclear magnetic resonance spectroscopy
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31P nuclear magnetic resonance (NMR) spectroscopy was used in conjunction with cell perfusion techniques to monitor the intracellular chemistry of the cyclophosphamide (CP, CAS 6055-19-2) metabolites 4-hydroxycyclophosphamide (4HO-CP) and aldophosphamide (AP) in U937 human histiocytic (CP-sensitive) and K562 human erythroleukemia (CP-resistant) cells. Similar experiments were carried out using the ifosfamide (IF, CAS 3778-73-2) metabolites 4-hydroxyifosfamide (4-HO-IF) and aldoifosfamide (AIF). The hydroxy and aldehydic metabolites were generated by the triphenylphosphine reduction of 4-hydroperoxycyclophosphamide (4-HO2-CP) or 4-hydroperoxyifosfamide (4-HO2-IF) or by a spontaneous elimination/addition reaction involving water and 4-thiocyclophosphamide analogs 4-(2-hydroxyethyl)thiocyclophosphamide (4-ESCP) or mafosfamide. Cell death resulting from 4-HO-CP/AP perfusions was mimicked by perfusion with acrolein or an acrolein producing but non-alkylating, dechloro-CP analog. Acrolein toxicity was minimized by the presence of 2-mercaptoethanol or mesna (sodium 2-mercaptoethanesulfonate) in perfusion solutions as well as by fractional dose drug perfusions (sequential 2.5-3.0 h perfusions separated by cell washes with drug-free medium). The intracellular half-life for phosphoramide rd (PM) at an intracellular pH value of 7.1 ± 0.1 and an ambient probe temperature of 23 ± 1°C in U937 cells was 2.1 h [k = (5.4 ± 0.3) x 10-3 min-1] and in K562 cells was 3.1 h [k = (3.7 ± 0.4) x 10-3 min-1]. Similar half-lives (2-4 h) were determined for intracellular isophosphoramide mustard (IPM). Fractional dose perfusion of U937 or K562 cells with 1.5 mmol/l 4-HO-CP/AP (generated from 4-HO2-CP) and 0.3 mmol/l mesna allowed for the observation of intracellular carboxyphosphamide (CBP); CBP was formed in higher concentrations in the CP-resistant K562 cells. Similar results were obtained using 4-ESCP and mafosfamide as sources of 4-HO-CP/AP. Identification of CBP was based on chemical shift, chemical stabiity, and membrane permeability studies of synthetic, CBP. Concentrations of carboxyifosfamide (CBIF) formed in K562 cells were also greater than that in U937 cells.
- Boal,Ludeman,Ho,Engel,Neimeyer
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