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Glycosidation, 13; anticancer agents, 10. Novel stable bioactivated cyclophosphamide derivatives for selective cancer chemotherapy, synthesis of aldophosphamide acetal‐glycosides and their glycoconjugates
Author(s) -
Tietze Lutz F.,
Fischer Roland,
Beller Matthias,
Seele Rainer
Publication year - 1990
Publication title -
liebigs annalen der chemie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 0170-2041
DOI - 10.1002/jlac.199019900126
Subject(s) - chemistry , prodrug , acetal , glycoside , stereochemistry , biochemistry
Stimulation of tumor cell glycolysis in vivo leads to an increase of lactic acid formation and thus a decrease of pH in malignant tissue compared with a normal cell population. The difference in pH may be used to cleave a nontoxic prodrug selectively in a tumor to give a highly cytotoxic compound. In this respect, acetal‐glycosides of aldophosphamide ( 3 ), a biological active metabolite of the anticancer agent cyclophosphamide ( 1 ) with α‐ D ‐ and β‐ D ‐glucose as well as α‐ D ‐mannose have been synthesized. Reaction of the trimethylsilyl glycosides 8a , 8b , and 8c with the acetals 9a , 9b , and 9c in the presence of TMS–OTf at −78°C gave selectively according to the anomeric center the acetal‐glycosides 10a – e in 68–88% yield. Debenzylation, reaction with the phosphorous acid amide dichloride 12 and ammonia, led to the aldophosphamide derivatives 15a – e . For coupling with biopolymers, the ester moiety in 15d and 15e was hydrolyzed to give 16a and 16b . As a model study, coupling of 16a and 16b with the lysine derivative 17 using 1‐hydroxybenzotriazol ( 18 ) and an excess of diisopropyl carbodiimide ( 19 ) was accomplished to afford 16c and 16d which were acetylated to give 16e and 16f .