High-resolution nuclear magnetic resonance investigations of the chemical stability of cyclophosphamide and related phosphoramidic compounds

Zon, Gerald; Ludeman, Susan M.; Egan, William

doi:10.1021/ja00459a041

Cited by 38 publications

(29 citation statements)

References 6 publications

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“…Since the P-N bonds in I are known to be sensitive to acid-catalyzed hydrolysis (27), the aforementioned results were consistent with the decomposition of IV to I and hydrofluoric acid, which then afforded hydrolytic products of the type previously found with I (27). Solutions of IV or IV-bovine serum albumin (201) in 0.1M NaCl gave results similar to those obtained in unbuffered water.…”

Section: Resultssupporting

confidence: 78%

Synthesis and Evaluation of 3-Halocyclophosphamides and Analogous Compounds as Novel Anticancer “Pro-Prodrugs”

Zon

Ludeman

Ӧzkan

et al. 1983

Journal of Pharmaceutical Sciences

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Section: Resultssupporting

confidence: 78%

Synthesis and Evaluation of 3-Halocyclophosphamides and Analogous Compounds as Novel Anticancer “Pro-Prodrugs”

Zon

Ludeman

Ӧzkan

et al. 1983

Journal of Pharmaceutical Sciences

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“…Subsequently, the kinetics and the reaction mechanism have been elucidated by sophisticated NMR studies. 39 In unbuffered aqueous solution at a temperature of 100 "C, 1 undergoes a rate-limiting carbonchlorine bond cleavage followed by an intramolecular alkylation of the endocyclic nitrogen, yielding the bicyclic phosphoramidate 4, which rapidly decomposes by hydrolytic cleavage of the two P-N bonds.…”

Section: Stereochemistrymentioning

confidence: 99%

A mass spectral study of cyclophosphamide concerning a thermally induced rearrangement reaction

Busker¹,

Koberstein²,

Niemeyer³

et al. 1988

Biol. Mass Spectrom.

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The electron impact mass spectra of cyclophosphamide (1) are very sensitive towards experimental conditions in view of the kind of sample handling, the type of mass spectrometer used and the temperature of evaporation. The reason for this phenomenon is the elimination of HCl from the molecular ion by a specific 1,5-hydrogen transfer yielding an ion at m/z 224 which is structurally related to the bicyclic compound 4 with its typical fragment ions at m/z 175 and 147. Thermal excitation of the sample increases the intensity of this fragmentation pathway. The fragmentation pattern of 1 and the thermally induced rearrangement reaction has been elucidated by means of isotopic labelling, high-resolution data, metastable ion analysis and some tandem mass spectrometric experiments. Various samples of 1 monohydrate and its commercially available preparations, which are triturates with sodium chloride, differing in the crystal size distribution, showed nearly identical mass spectra on two different magnetic mass spectrometers, provided that the materials were introduced as solids under careful control of the evaporation temperature. The fragmentation via m/z 224 prevails in case of non-crystalline, pre-dissolved samples on one of the instruments used which might be explained by a differing construction of the ion source and the sample cup holder. The conclusions of Mruzek et al. concerning different proportions of stereoisomers in pharmaceutical preparations of 1 lack any analytical evidence.

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“…Such cyclization was in fact postulated (4) and demonstrated (5) for the nonenzymatic hydrolysis of cyclophosphamide itself. Similarly, a compound like 2 may undergo a nucleophilic ring opening reaction not only with an external nucleophile, but via the attack of the endocyclic nitrogen, yielding the isomeric 1,3,2-diazaphospholidine skeleton.…”

mentioning

confidence: 94%

“…Similarly, a compound like 2 may undergo a nucleophilic ring opening reaction not only with an external nucleophile, but via the attack of the endocyclic nitrogen, yielding the isomeric 1,3,2-diazaphospholidine skeleton. Such an intramolecular 1,5 opening of the aziridine ring was postulated (2) in the 31P n~n r spectroscopic study on the chemistry of phosphoramide mustard derivatives.…”

mentioning

confidence: 99%

Phosphoric amides. Part 11. Intramolecular reactivity of phosphorotriamidates

Bauermeister¹,

Modro²,

Modro³

et al. 1991

Can. J. Chem.

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SIEGELINDE BAUERMEISTER, AGNES M. MODRO, TOM A. MODRO, and ANDRZEJ ZWIERZAK. Can. J. Chem. 69,811 (1991). Five N-(2-chloroethyl)phosphorotriamidates, (RNH)2P(0)NHCH2CH2Cl, have been synthesized, and their behavior under strongly basic conditions was studied. For N-alkyl derivatives (R = Me, PhCH2), base-promoted intramolecular displacement of chloride yielded the N-phosphorylated aziridine, (RNH)?P(0)NC2H4, as the exclusive cyclization product. For N-aryl derivatives (R = Ar), both the aziridine and the 1,3,2-diazaphospholidine, RNHP(0)NHCH2CH2NR, products could be obtained in comparable yields. The N-aromatic cyclic products are mutually interconvertible: 1,3,2-diazaphospholidines rearrange to the corresponding aziridines upon treatment with base, while bromide ions catalyze the reverse isomerization.Key words: phosphoramidates acidity, N-phosphorylated aziridines -1,3,2-diazaphospholidines isomerization, 1,3 vs. 1,5 cyclization.SIEGELINDE BAUERMEISTER, AGNES M. MODRO, TOM A. MODRO et ANDRZEJ ZWIERZAK. Can. J. Chem. 69, 81 1 (1991). On a rCalisC la synthkse de cinq N-(2-chlorokthyl)phosphorotriamidates, (RNH)2P(0)NHCH2CH2C1, et on a CtudiC leur comportement dans des conditions fortement basiques. Pour les dCrivCs N-alkylCs (R = Me, PhCH2), le dCplacement intramolkculaire du chlorure, catalysC par les bases, fournit l'aziridine N-phosphorylke, (RNH)2P(0)NC2H4, comme seul produit de cyclisation. Pour les dCrivCs N-arylks (R = Ar), on peut obtenir avec des rendements comparables l'aziridine ainsi que la 1,3,2-diazaphospholidine, RNHP(O)NHCH?CH~NR. Les produits cycliques N-aromatiques sont mutuellement interconvertibles; les 1,3,2-diazaphospholidines se transposent en aziridines correspondantes par traitement avec des bases alors que les ions bromures catalysent l'isomtrisation inverse.Mots elks : acidit6 de phosphoramidates, isomerisation aziridines N-phosphorylCes -1,3,2-diazaphospholidines, cyclisations 1,3 vs. 1,5.[Traduit par la rkdaction]The phosphoramide mustard 1 is believed to be the active metabolite d t h e anti-tumor alkylating drug, cyclophosphamide, its cytotoxic action involving the cross-linking produced in cellular DNA (1). The alkylating reactivity of 1 is attributed to its intramolecular cyclization to-the aziridinium ion, followed by the intermolecular reaction of that intermediate with a biological nucleophile (2). N-Phosphorylated aziridines (e.g., aphamide 2 ) are known inhibitors of cell division, the property Intramolecular reactivity of a system of type 1 can, however, involve not only the 1,3 displacement of chloride ion (aziridinium ion formation), but also the 1,5 substitution in the NPNCCCl system, yielding the 1,3,2-diazaphospholidine product.Such cyclization was in fact postulated (4) and demonstrated (5) for the nonenzymatic hydrolysis of cyclophosphamide itself. Similarly, a compound like 2 may undergo a nucleophilic ring opening reaction not only with an external nucleophile, but via the attack of the endocyclic nitrogen, yielding the isomeric 1,3,2-diazaphospholidine skeleton. Su...

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High-resolution nuclear magnetic resonance investigations of the chemical stability of cyclophosphamide and related phosphoramidic compounds

Cited by 38 publications

References 6 publications

Synthesis and Evaluation of 3-Halocyclophosphamides and Analogous Compounds as Novel Anticancer “Pro-Prodrugs”

Synthesis and Evaluation of 3-Halocyclophosphamides and Analogous Compounds as Novel Anticancer “Pro-Prodrugs”

A mass spectral study of cyclophosphamide concerning a thermally induced rearrangement reaction

Phosphoric amides. Part 11. Intramolecular reactivity of phosphorotriamidates

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