Glycosidation, 13; anticancer agents, 10. Novel stable bioactivated cyclophosphamide derivatives for selective cancer chemotherapy, synthesis of aldophosphamide acetal-glycosides and their glycoconjugates
✍ Scribed by Tietze, Lutz F. ;Fischer, Roland ;Beller, Matthias ;Seele, Rainer
- Publisher
- John Wiley and Sons
- Year
- 1990
- Tongue
- English
- Weight
- 826 KB
- Volume
- 1990
- Category
- Article
- ISSN
- 0947-3440
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✦ Synopsis
Abstract
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.