Prodrugs glycoside

C. P. Landowski, X. Song, P. L. Lorenzi, J. M. Hilfinger, and G. L. Amidon. Flox-uridine amino acid ester prodrugs enhancing Caco-2 permeability and resistance to glycosidic bond metabolism. Pharm Res 22 1510-1518 (2005). 

Tafluposide (F 11782) is an epotoside (epipodophyllotoxin) derivative (cf. Chapter 4) where the two hydroxyls of the glycosidic moiety are acylated with pentafluorophenoxyacetic acid (Figure 8.7). It has been demonstrated that tafluposide does not act as a prodrug of epotoside, but it has a unique mechanism of interaction with both topoisomerases I and... 

Similar to glycoside prodrugs are the glucuronide prodrugs containing corticosteroids [53-55], They also show improvements in the therapeutic effect and in the reduction of side effects. 

Another prodrug of 54c is compound 55. Prodrug 55, which contains an aromatic and aliphatic bis-carbamate spacer, is activated by (3-glucuronidase (Scheme 23).86 A rapid cleavage of the glycosidic bond occurred (tj/2 = 6.6 minutes) with concomitant appearance of intermediate 55c, of which the ethylene diamine spacer cyclized with a half-life of 2 hours. The cytotoxicity of 55 against LoVo cells was about 50 times less than that of the corresponding phenol mustard 54c. 

Friend DR, Chang GW. Drug glycosides potential prodrugs for colon-specific drug delivery. J Med Chem 1985 28 51-57. 

An important point for non-toxic prodrug design is the choice of the substitution site of the drug by the enzyme substrate. The type and stereochemistry of the substituents at C-9 on the A-ring of anthracyclines has been shown to have a dramatic influence on activity of these antibiotics [1-4]. Efficient detoxification could therefore be expected by glycosidation of the 14-OH group of doxorubicin by a bulky sugar unit. 

The synthesis of prodrug 13 first involved condensation of penta-0-acetyl-D-galactose (15) with para-cresol (16), in the presence of ZnCl2 [56, 57], to afford stereospecifically the a-glycoside 17 [58]. Benzylic bromination of 17 was achieved by treatment with iV-bromosuccinimide in carbon tetrachloride under photolysis conditions. Solvolysis of the bromobenzyl derivative 18 by treatment with silver nitrate in a mixture of acetone and water afforded alcohol 19 [59], which was subsequently activated through reaction with A -hydroxysuccinimidocarbonate to 20. 

Thus, glycosidation of 2-chloro-4-methylphenol (32) by penta-O-acetyl-D-galactose (15) in the presence of zinc chloride afforded 33, which was subsequently submitted to benzylic bromination to 34. Solvolysis of 34 to 35 was followed by activation using N, iV-disuccinimidylcarbonate (DSC) to give 36. This intermediate was in turn condensed without purification with daunorubicin (1) to yield 37. Final deprotection by transesterification afforded prodrug 29. 

In order to determine if this lack of significant enzymatic activity was related to the steric hindrance or to the nature of the carbamate ester glycosidic linkage, synthesis of the bis-carbamate prodrug 52 was undertaken [63]. 

Most glycosides can be classed as prodrugs since they remain inactive until they are hydrolysed in the large bowel with the help of specialised bacteria, leading to the release of the aglycone—the truly active constituent. 

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