| Chemical characterization of ASTA Z 7557 (INN mafosfamide, CIS-4-sulfoethylthio-cyclophosphamide), a stable derivative of 4-hydroxy-cyclophosphamide. | |
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MedLine Citation:
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PMID: 6469506 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The primary metabolite of cyclophosphamide (CP, 1), i.e. 4-hydroxy-CP 2, has high pharmacological activity, but it is a very unstable compound. Chemical approaches to the stabilization involved in the substitution of the hydroxy group at the C 4-position, especially by a sulfoalkylthio-moiety. Within this new class of compounds ASTA Z 7557 (2-(bis-(2-chloroethyl]-amino-cis-4-[2-sulfoethyl)-thio)-tetrah ydr o-2H-1,3, 2-oxaza-phosphorine-r-2-oxide cyclohexylamine salt, i.e. cis-4-sulfoethylthio-CP, cis-13) was chosen for further evaluation. Cis-13 was synthesized by condensation of compound 2 and 2-mercapto-ethanesulfonic acid cyclohexylamine salt 14 in aqueous acetone yielding the cis-isomer with high stereoselectivity. It is a white crystalline powder, m.p. 126-134 degrees C, stable at room temperature, with a solubility of 16% in water. The stereochemistry was confirmed by NMR-data and X-ray diffraction. In 0.07 M phosphate buffer at pH 7 and 37 degrees C cis-13 isomerizes to the epimer trans-13, equilibrating at a cis-trans-ratio of 59 to 41 within less than 5 minutes. Simultaneously a rapid initial hydrolysis occurs to 2 and 14 followed by a time period with lower degradation due to the decomposition of 2. The rate of release of 2 increases with decreasing concentration and especially by addition of an oxidant. It could be retarded by addition of the corresponding thiol mesna, sodium 2-mercapto-ethanesulfonate 15, or of another thiol.(ABSTRACT TRUNCATED AT 250 WORDS) |
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Authors:
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U Niemeyer; J Engel; G Scheffler; K Molge; D Sauerbier; W Weigert |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Investigational new drugs Volume: 2 ISSN: 0167-6997 ISO Abbreviation: Invest New Drugs Publication Date: 1984 |
Date Detail:
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Created Date: 1984-10-01 Completed Date: 1984-10-01 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8309330 Medline TA: Invest New Drugs Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 133-9 Citation Subset: IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Biotransformation Cyclophosphamide / analogs & derivatives*, analysis, chemical synthesis, metabolism* Hydrogen-Ion Concentration Hydrolysis Kinetics Stereoisomerism Temperature |
| Chemical | |
Reg. No./Substance:
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40277-05-2/4-hydroxycyclophosphamide; 50-18-0/Cyclophosphamide; 88746-71-8/Asta Z 7557 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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