Glycosidation, 13; anticancer agents, 10. Novel stable bioactivated cyclophosphamide derivatives for selective cancer chemotherapy, synthesis of aldophosphamide acetal‐glycosides and their glycoconjugates

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 CL-D-and P-D-glucose as well as a-D-mannose have been synthesized. Reaction of the trimethylsilyl glycosides 8a, 8b, and 8c with the acetals 9a, 9b, and 9c in the Cyclophosphamide (1) is one of the most effective anticancer agents with proven activity against a large variety of human cancers *). Its bioactivation through enzymatic hydroxylation at C-4 by hepatic mixed function oxidases, mainly in the liver, affords 4-hydroxycyclophosphamide (2), which is in equilibrium with aldophosphamide (3). A rapid elimination of acrolein (4) gives the phosphoramide mustard 5, which may react directly or after formation of an aziridinium salt 6 with DNA or 3'5'-exonu~leases~.~). The use of aldophosphamide (3) as an anticancer agent is usually not possible because of its pronounced chemical lability which so far has prevented an isolation of the free compound4'. Therefore, a reversible blocking of the aldehyde function in 3, e.g. as an acetal-glycoside5), should give a nontoxic prodrug for cancer chemotherapy. Aldophosphamide could be released from such a compound either by acid-catalyzed or pH-selective enzymatic hydrolysis, since it has been shown that by stimulation of tumor-cell glycolysis in vivo, an increase of lactic acid formation and thus a decrease of pH in malignant tissue, as compared with normal tissue, can be observed. Thus, a selective cleavage of the prodrug may be possible in tumors. Recently'), we described the synthesis of the hexenopyranoside 7 of aldophosphamide and its in vitro-proton-mediated cleavage to give aldophosphamide (3). The survival curves of M1R tumor cells exposed to 7 at pH = 7.4 (pH of serum) and of pH = 5.6 as well as of pH = 6.2 (pH in tumors with hyperglycemia) showed an astounding selectivity depending on the pH of the cell culture. The surviving fraction of M1R cells decreased to less than I V 5 of untreated controls at pH = 5.6 (10 pg/rnI) for 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.24 hours and at pH = 6.2 (10 pg/ml) for 48 hours exposure time, whereas at pH = 7.4 only very limited cytotoxicity, even after exposure...

Intensely Cytotoxic Anthracycline Prodrugs: Glucuronides

“…The assignment of the configuration of these compounds is based on their 1 H NMR spectra and a comparison of these data with the published data of similarly constituted compounds. Thus, Tietze et al established NMR rules ,− for the determination of the configuration of acetal glucosides. According to these rules, the 1‘-H signals for (l R ,l‘ R )- and (l S ,l‘ S )-glycosides occur at lower fields than those of their l R ,l‘ S and l S ,1‘ R counterparts.…”

Nitrobenzyl-Based Photosensitive Phosphoramide Mustards: Synthesis and Photochemical Properties of Potential Prodrugs for Cancer Therapy

“…Most of the phosphoramide mustard-derived reagents in and of themselves are inactive “prodrugs”. They are activated by different mechanisms that involve hydrolytic, bioreductive, and biooxidative pathways. Interestingly, photochemical activation of alkylating species has not been developed, despite the potential advantage of controllable release.…”

Transport of the new chemotherapeutic agent β- d -glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na + - d -glucose cotransporter SAAT1

“…started a program to study carrier systems for drugs. At variance to a series of other reports where monosaccharides were used as carriers (2,3), M.W. decided to connect therapeutically active compounds to the 1-position of the carbohydrate skeleton (4).…”