Behaviour of an aziridine alkylating agent in acid solution

Maxwell, John P.; Kaushik, Durga S.; Butler, C. G.

doi:10.1016/0006-2952(74)90324-4

Cited by 12 publications

(1 citation statement)

References 4 publications

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“…Other pathways that could be sources of alkylating ability of thiotepa may involve reactive intermediates, including proposed cyclic intramolecular S-alkylated rearrangement products (17,18) and ring-opened (chloroethyl)phosphoramides generated in the presence of chloride ion (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N''-triethylenethiophosphoramide

Musser¹,

Pan²,

Egorin³

et al. 1992

Chem. Res. Toxicol.

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A reaction pathway by which thiotepa (N,N',N''-triethylenethiophosphoramide) and tepa (N,N',N''-triethylenethiophosphoramide), its major metabolite in humans, alkylate and depurinate DNA involves hydrolysis to aziridine (ethylene imine), a highly reactive monofunctional alkylating agent. Hydrolytic cleavage of an N-P bond of thiotepa releases aziridine which reacts with DNA, resulting in depurination and formation of the stable N-7 adduct 7-(2-aminoethyl)guanine and an aminoethyl adduct of adenine. Chromatographically identical alkylated products were observed in the reaction of thiotepa and tepa with individual nucleosides. Adducts with deoxycytidine or thymidine were not detected. Aziridine was measured by HPLC after derivatization with 1,2-naphthoquinone 4-sulfate. On the basis of the identity of the DNA adducts and the rate of formation of aziridine by hydrolysis in vitro, thiotepa is concluded to be a lipophilic, stabilized form of aziridine which serves as a cell-penetrating carrier of aziridine.

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Section: Introductionmentioning

confidence: 99%

Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N''-triethylenethiophosphoramide

Musser¹,

Pan²,

Egorin³

et al. 1992

Chem. Res. Toxicol.

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Hydrolysis of 1,1˙,1″-phosphinothioylidinetrisaziridine (thiotepa) in aqueous solution

Pyatigorskaya¹,

Zhilkova²,

Shelkovsky³

et al. 1987

Biol. Mass Spectrom.

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The behaviour of 1,1',1"-phosphinothioylidinetrisaziridine (thiotepa) in water and aqueous salt solution of various acidity was studied by field ionization mass spectrometry (FI-MS), TLC and potentiometric titration. The rate of thiotepa hydrolysis increased with increasing thiotepa, or sodium chloride concentration, and with decreasing pH. As hydrolysis products of thiotepa, monoand dichloro derivatives formed in neutral, salt-containing and acidic solution, tepa, and products formed by P-N bond cleavage and release of aziridine have been identified.

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Investigation of the stability of triethylenethiophosphoramide in aqueous and aqueous salt solutions

et al. 1984

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Behaviour of an aziridine alkylating agent in acid solution

Cited by 12 publications

References 4 publications

Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N''-triethylenethiophosphoramide

Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N''-triethylenethiophosphoramide

Hydrolysis of 1,1˙,1″-phosphinothioylidinetrisaziridine (thiotepa) in aqueous solution

Investigation of the stability of triethylenethiophosphoramide in aqueous and aqueous salt solutions

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