Phosphorus-31 NMR investigations of phosphoramide mustard: evaluation of pH control over the rate of intramolecular cyclization to an aziridinium ion and the hydrolysis of this reactive alkylator

Engle, T. W.; Zon, Gerald; Egan, William

doi:10.1021/jm00194a001

Cited by 18 publications

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“…The latter can be oxidized by aldehyde dehydrogenase (ALDH) to give inactive carboxyifosfamide, a cause of chemoresistance, or it can decompose by 1-elimination to give isophosphoramide mustard (IPM), the primary alkylating agent. The IPM has a PKa of 4.75 and is membrane impermeable (Engle et al, 1979) and therefore has to be formed intracellularly for its cytotoxic action. Secondly, up to 50% of IF can undergo spontaneous oxidative dealkylation to give 2-or 3-dechloroethylifosfamide (2-DCI or 3-DCI) and chloroacetaldehyde, a compound with possible neurotoxic properties.…”

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confidence: 99%

In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas

Rodrigues

Maxwell²,

McSheehy³

et al. 1997

Br J Cancer

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SummaryThe direct detection and monitoring of anti-cancer drugs in vivo by magnetic resonance spectroscopy (MRS) may lead to improved anti-cancer strategies. 31P-MRS has been used to detect and quantify ifosfamide (IF) in vivo in GH3 prolactinomas and N-methyl-Nnitrosourea (MNU)-induced mammary tumours in rats. The average concentration of IF in the GH3 prolactinoma over the first 2 h following a dose of 250 mg kg-' i.v. was calculated to be 0.42 ,umol g-1 wet weight, with a half-life of elimination (t,,2) of 2-4 h. Carbogen (95% oxygen/5% carbon dioxide) breathing increased the amount of IF taken up by the GH3 prolactinoma by 50% (P<0.01) to 0.68 ,umol g-1 wet weight, although t,,2 elimination rates were unchanged. IF was also detected in the liver in vivo, with a t,,c of about 1 h. Carbogen breathing did not affect the maximum peak area (Cmax) or the t,,2 in the liver. Most importantly, the carbogen-induced increase in IF uptake by the tumour caused significant growth delay at all time points in the GH3 tumour growth between day 5 and day 12 (P < 0.01) compared with IF alone. These findings show that carbogen breathing has potential for increasing the efficacy of anti-cancer drugs. Isolated GH3 cells were sensitive to the parent drug (IF) in vitro (C~50 = 1.3 ± 0.2 mM) suggesting that the GH3 cells may be either expressing P450 enzymes or are sensitive to the parent drug per se.

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confidence: 99%

In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas

Rodrigues

Maxwell²,

McSheehy³

et al. 1997

Br J Cancer

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“…While an influence of pH on the alkylating activity of PM is expected based on first-principles of organic chemistry, no data was available at the time. Briefly, as we reported in 1979 (Engle et al 19 ), the 31 P-NMR kinetic data for PM demonstrated that the half-life of this metabolite of CP exhibits appreciable variation (~5-fold decrease) over the physiologically relevant pH range of 6-8, and that the anionic conjugate base of PM (PM-) is the required precursor to its intramolecularly cyclized aziridinium ion species (Scheme 2). The relative concentration of this aziridinium ion reached a peak that was also dependent on pH, increasing with lower pH.…”

Section: Nmr Spectroscopic Elucidation Of Cp Metabolites and Kineticsmentioning

confidence: 63%

Chemistry, Cyclophosphamide, Cancer Chemotherapy, and Serendipity: Sixty Years On

Зон¹

2021

Substantia

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Cambridge Dictionary: serendipity | noun | the phenomenon of finding interesting or valuable things by chance. The year 2019 marked the 60th anniversary of the approval of cyclophosphamide (CP) as an anticancer by the U.S. Food & Drug Administration in 1959 for the treatment of lymphoma. Between 1959 and 2019 there were ~50,000 publications listed in PubMed that have CP in the title and/or abstract, with these annual numbers showing a continual increase, and over 1,800 such articles in 2019 alone. The discovery of CP is a prime example of serendipity in science, which also applies to key elements of the metabolism and pharmacological basis for the specificity of the cytotoxicity of CP toward cancer cells. Phosphoramide mustard (PM), HO(H2N)P(O)N(CH2CH2Cl)2, the principal metabolite of CP with DNA alkylating activity, was synthesized and reported by Friedman and Seligman in 1954 prior to the discovery of CP. Interestingly, the original drug design premise for synthesizing PM, which was based on elevated phosphamidase enzyme activity in cancer cells proved to be incorrect. While this wrong premise also led to the synthesis of CP, as a six-membered ring cyclic phosphamidase-activated precursor of PM, the actual metabolic conversion of CP to PM was subsequently found to involve a surprisingly complex array of metabolites and metabolic pathways, all completely unrelated to phosphamidase. Although the molecular structure of CP has an asymmetrically substituted, i.e. chiral phosphorus center, the racemic mixture of the Rp and Sp enantiomers of CP was used throughout its initial investigations and subsequent clinical trials despite the involvement of an initial enzyme-mediated metabolic activation step, which could, in principle, be stereoselective for only one of the enantiomers of CP. Stereochemical investigations along those lines were eventually carried out, but the results did not warrant replacement of racemic CP with either enantiomer in the clinic. Amazingly, there are now ~4,000 structural congeners of PM listed Chemical Abstracts, but none have led to an anticancer drug superior to CP. This account provides a synopsis of the key chemistry and stereochemistry investigations that comprise this story of CP, as a remarkable instance of serendipity in science, and my chance involvement in the unfolding of this fascinating story.

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“…Hydroxyphosphamide (6 21.01), which is the 3-hydroxypropyl analog of aldophosphamide (III), is a good chemical shift model for 31P-NMR identification of 111; however, it should be noted that the proportion of free aldehyde in 111 uersus its hydrate (15) has not been established. The absolute and relative signal intensities for cis-11, trans-11, and 111 vary (not shown) during the course of their gradual tautomerization and fragmentation of 111 to give IV and V, which is relatively short-lived and was previously studied by 31P-NMR (16). In contrast to these spectral changes, addition of a 5-fold molar excess of 0-methylhydroxylamine hydrochloride leads to rapid ( < l o min) consumption of II/III with formation of a single resonance (6 20.83) due to the E and Z aldophosphamide 0-methyl oxime (XI and XII) trapping products (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4-ketocyclophosphamide (XIV) ( l l ) , and compound XV (12) were synthesized and compound XI11 was prepared and purified by Colvin's' method. "P-Fourier-transform NMR spectra at 40.25 MHz2 were obtained using 10-mm sample tubes, a 5-kHz spectral window, 8192 data points zero-filled to 16 broadened by 1 Hz due to exponential multiplication prior to Fouriertransform. 31P-Fourier-transform NMR spectra a t 121.5 MHz3 were recorded in a similar manner except for the use of a 20-psec 7~/2 pulse, a 1.4-sec pulse repetition time, and 2.5 Hz of line-broadening.…”

Section: Methodsmentioning

confidence: 99%

O-Methylhydroxylamine as a New Trapping Reagent for Quantitative Studies of 4-Hydroxycyclophosphamide and Aldophosphamide

Zon

Ludeman

Sweet

et al. 1982

Journal of Pharmaceutical Sciences

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Phosphorus-31 NMR investigations of phosphoramide mustard: evaluation of pH control over the rate of intramolecular cyclization to an aziridinium ion and the hydrolysis of this reactive alkylator

Cited by 18 publications

References 0 publications

In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas

In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas

Chemistry, Cyclophosphamide, Cancer Chemotherapy, and Serendipity: Sixty Years On

O-Methylhydroxylamine as a New Trapping Reagent for Quantitative Studies of 4-Hydroxycyclophosphamide and Aldophosphamide

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