119321-14-1

Upstream product

• 34637-22-4 3-[(N-benzyloxycarbonyl)amino]propanol 
• 86520-63-0 2,3,4,6-tetra-O-acetyl-α-galactopyranosyl trichloroacetimidate 
• 70191-05-8 2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 
• 4163-60-4 β-D-galactose peracetate 

Relevant academic research and scientific papers

Synthesis and enzyme-specific activation of carbohydrate-geldanamycin conjugates with potent anticancer activity

Geldanamycin (GA) is a potent anticancer antibiotic that inhibits Hsp90. Its potential clinical utility is hampered by its severe toxicity. To alleviate this problem, we synthesized a series of carbohydrate-geldanamycin conjugates for enzyme-specific activation to increase tumor selectivity. The conjugation was carried out at the C-17-position of GA. Their anticancer activity was tested in a number of cancer cell lines. The enzyme-specific activation of these conjugates was evaluated with β-galactosidase and β-glucosidase. Evidently, glycosylation of C-17-position converted GA to an inactive prodrug before enzyme cleavage. Glucose-GA, as positive control, showed anticancer activity with IC50 of 70.2-380.9 nM in various cancer cells by β-glucosidase activation inside of the tumor cells, which was confirmed by 3-fold inhibition using β-glucosidase specific inhibitor [2,5-dihydroxyniethy-3,4-dihydroxypyrrolidine (DMDP)]. Compared to glucose-GA, galactose- and lactose-GA conjugates exhibited much less activity with IC 50 greater than 8000-25 000 nM. However, when galactose- and lactose-GA were incubated with β-galactosidase in the cells, their anticancer activity was enhanced by 3- to 40-fold. The results suggest that GA can be inactivated by glycosylation of C-17-position and reactivated for anticancer activity by β-galactosidase. Therefore, galactose-GA can be exploited in antibody-directed enzyme prodrug therapy (ADEPT) with β-galactosidase for enzyme-specific activation in tumors to increase tumor selectivity.

METHODS AND COMPOSITIONS FOR ENZYME-SPECIFIC ACTIVATION OF CARBOHYDRATE-CONJUGATED PRODRUGS

Methods for the targeted activation of prodrugs by enzymes, which cleave a linkage between a carbohydrate conjugate and a drug. Means to target the activation of prodrugs to specific cells by linking the enzyme to an antibody molecule. Carbohydrate conjugates of geldanamycin.