Journal article
Synthesis and enzyme-specific activation of carbohydrate-geldanamycin conjugates with potent anticancer activity
Journal of medicinal chemistry, Vol.48(2), pp.645-652
01/27/2005
Handle:
https://hdl.handle.net/2376/108836
PMID: 15658879
Abstract
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 beta-galactosidase and beta-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 IC(50) of 70.2-380.9 nM in various cancer cells by beta-glucosidase activation inside of the tumor cells, which was confirmed by 3-fold inhibition using beta-glucosidase specific inhibitor [2,5-dihydroxymethy-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 beta-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 beta-galactosidase. Therefore, galactose-GA can be exploited in antibody-directed enzyme prodrug therapy (ADEPT) with beta-galactosidase for enzyme-specific activation in tumors to increase tumor selectivity.
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Details
- Title
- Synthesis and enzyme-specific activation of carbohydrate-geldanamycin conjugates with potent anticancer activity
- Creators
- Hao Cheng - Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USAXianhua CaoMing XianLanyan FangTingwei Bill CaiJacqueline Jia JiJosefino B TunacDuxin SunPeng George Wang
- Publication Details
- Journal of medicinal chemistry, Vol.48(2), pp.645-652
- Academic Unit
- Chemistry, Department of
- Publisher
- United States
- Identifiers
- 99900546891001842
- Language
- English
- Resource Type
- Journal article