Stereospecific synthesis of tetradeuterated (R)- and (S)-ifosfamide

Wang, Jeff J.-H.; Chan, Kenneth K.

doi:10.1002/(sici)1099-1344(199602)38:2<105::aid-jlcr821>3.0.co;2-x

Cited by 8 publications

(10 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that 4‐OH‐CP exists as two tautomeric forms in solution, the ring‐opened aldehyde form (aldophosphamide or aldo P) and the ring‐closed form (4‐OH‐CP) 9, 17. In solution, it has been shown that aldo P readily undergoes β ‐elimination to eliminate acrolein (CH 2 CHCHO) to form PM 8, 16. The MS 2 spectrum (Table 1) of the MH + ion of 4‐OH‐CP/aldo P at m/z 277 shows the most abundant fragment ion at m/z 221.0, a loss of 56 Da corresponding to acrolein.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites

Liu

Chan

Wang

2005

Rapid Comm Mass Spectrometry

Self Cite

View full text Add to dashboard Cite

A detailed multi-stage (MSn) fragmentation study of cyclophosphamide (CP), ifosfamide (IF) and their major metabolites, using an ion-trap mass spectrometer and a Q-TOF mass spectrometer, was performed with the aid of specifically deuterium-labeled analogs. The analytes showed good responses in positive-ion electrospray mass spectrometry as [MH]+ ions. Tandem mass spectra revealed a wealth of structurally specific ions, allowing characterization of the fragmentation pathways of these analytes. The major fragmentation pathways of the protonated CP and IF are elimination of ethylene from C5 and C6 of 1,3,2-oxazaphosphorine-2-oxide via a McLafferty rearrangement, and cleavage of the P-N bond. However, their activated 4-OOH and 4-OH metabolites primarily underwent hydrogen peroxide elimination and dehydration, respectively, followed by fragmentation pathways similar to those of CP and IF. These results should prove useful in structural elucidation of future analogs of CP and IF, and/or of their metabolites.

show abstract

Section: Resultsmentioning

confidence: 99%

“…CP ( 1 ) and IF ( 2 ) were provided by the U.S. National Cancer Institute, and compounds 3 and 4 and all deuterium‐labeled compounds ( 1a , 1b , 2a and 5 , Scheme ) were synthesized as described 8. Compounds 3a and 4a were generated in situ from 3 and 4 , respectively, in the reaction medium.…”

Section: Methodsmentioning

confidence: 99%

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites

Liu

Chan

Wang

2005

Rapid Comm Mass Spectrometry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The triphenylmethyl (trityl) group is a useful protecting group for primary amines that can be easily and quantitatively removed using 1N–6N aqueous HCl and as such was suitable for our research needs. A search of the literature revealed no reports of N 1 ‐tritylethane‐1,1,2,2‐ d 4 ‐1,2‐diamine, but the di‐deuterated analog 2‐(tritylamino)ethan‐ 1 , 1‐d 2 ‐ol has been previously reported . That material was synthesized in two steps by the reaction of trityl chloride with ethyl glycine ester hydrochloride, followed by reduction of the ester carbonyl with lithium aluminum deuteride.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of N¹‐tritylethane‐1,1,2,2‐d₄‐1,2‐diamine: a novel mono‐protected C‐deuterated ethylenediamine synthon

Yang

Hong

Bonnesen

2012

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

A convenient and high‐yield synthesis for N1‐tritylethane‐1,1,2,2‐d4‐1,2‐diamine, a novel mono‐protected ethylenediamine‐C‐d4, is reported. N1‐tritylethane‐1,1,2,2‐d4‐1,2‐diamine was prepared in three steps from ethylene oxide‐d4 in a combined yield in the range 68–76%. Also reported is a synthesis of ethylenediamine‐C‐d4 in two steps from 1,2‐dibromoethane‐d4 in a combined yield in the range 61–65%.

show abstract

“…(R)-IFA and (S )-IFA, (R)-and (S )-6,6,2 0 ,2 0 -tetradeuterioIFA [(R)-and (S)-IFA-d 4 ] were synthesized in Dr. Chan's laboratory (Wang and Chan 1996). Both chemical and isotopic purities were >99.5% as determined by GC/MS analysis.…”

Section: Chemicalsmentioning

confidence: 99%

Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6

et al. 2006

View full text Add to dashboard Cite

The aim was to identify the hepatic cytochromes P450 (CYPs) responsible for the enantioselective metabolism of ifosfamide (IFA). The 4-hydroxylation, N2- and N3-dechloroethylation of IFA enantiomers were monitored simultaneously in the same metabolic systems using GC/MS and pseudoracemate techniques. In human and rat liver microsomes, (R)-IFA was preferentially metabolized via 4-hydroxylation, whereas its antipode was biotransformed in favour of N-dechloroethylation. CYP3A4 was the major enzyme responsible for metabolism of IFA enantiomers in human liver. The study also revealed that CYP3A (human CYP3A4/5 and rat CYP3A1/2) and CYP2B (human CYP2B6 and rat CYP2B1/2) enantioselectively mediated the 4-hydroxylation, N2- and N3-dechloroethylation of IFA. CYP3A preferentially supported the formation of (R)-4-hydroxyIFA (HOIF), (R)-N2-dechloroethylIFA (N2D) and (R)-N3-dechloroethylIFA (N3D), whereas CYP2B preferentially mediated the generation of (S)-HOIF, (S)-N2D and (S)-N3D. The enantioselective metabolism of IFA by CYP3A4 and CYP2B1 was confirmed in cDNA transfected V79 cells.

show abstract

Stereospecific synthesis of tetradeuterated (R)- and (S)-ifosfamide

Abstract: SummaryThe tetradeuterated analogues of (R)-and (S)-ifosfamide [(S)-and (R)-2-(2-chloro-2,2-

Cited by 8 publications

References 14 publications

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites

Synthesis of N¹‐tritylethane‐1,1,2,2‐d₄‐1,2‐diamine: a novel mono‐protected C‐deuterated ethylenediamine synthon

Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6

Contact Info

Product

Resources

About

Stereospecific synthesis of tetradeuterated (R)- and (S)-ifosfamide

Abstract: SummaryThe tetradeuterated analogues of (R)-and (S)-ifosfamide [(S)-and (R)-2-(2-chloro-2,2-

Cited by 8 publications

References 14 publications

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites

Synthesis of N1‐tritylethane‐1,1,2,2‐d4‐1,2‐diamine: a novel mono‐protected C‐deuterated ethylenediamine synthon

Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6

Contact Info

Product

Resources

About

Synthesis of N¹‐tritylethane‐1,1,2,2‐d₄‐1,2‐diamine: a novel mono‐protected C‐deuterated ethylenediamine synthon