Galactose prodrugs

HDLs tend to accumulate in the parenchymal fiver cells and target specific recognition moieties such as galactose can enhance the hepatocyte uptake process. This system is being investigated for the targeting of hydrophobic antiviral prodrugs to parenchymal fiver cells in viral hepatitis. 

The first two prodrugs we prepared using this concept 13 and 14, associated a-D-galactose as specifier with a para- or ortho-hydroxybenzyl spacer linked to daunorubicin through a carbamate group (54-55). 

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. 

Penta-O-acetyl-D-galactose (15) was first converted to 2,3,4,6-tetra-O-acetyl-a-D-galactopyranose (49) by treatment with hydrazine acetate in DMF [64]. Reaction of 49 with 4-nitrophenylchloroformate at 0°C in dichloromethane gave the stable 4-nitrophenyl (2,3,4,6-tetra-O-acetyl-a-D-galactopyranosyl) carbamate (50), which was condensed with doxorubicin (2) to afford 51. Transesterification of 51 using sodium methoxide in methanol provided the required prodrug 48 [63]. 

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