title: Synthesis and enzyme-specific activation of carbohydrate-geldanamycin conjugates with potent anticancer activity.
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.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.forename: Xianhua
authors.initials: X
authors.lastname: Cao
authors.forename: Ming
authors.initials: M
authors.lastname: Xian
authors.forename: Lanyan
authors.initials: L
authors.lastname: Fang
authors.forename: Tingwei Bill
authors.initials: TB
authors.lastname: Cai
authors.forename: Jacqueline Jia
authors.initials: JJ
authors.lastname: Ji
authors.forename: Josefino B
authors.initials: JB
authors.lastname: Tunac
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016227:Benzoquinones; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005690:Galactose / Q000737:chemistry*; D006801:Humans; D050113:Imino Furanoses; D047029:Lactams, Macrocyclic; D007785:Lactose / Q000737:chemistry*; D008353:Mannitol / Q000031:analogs & derivatives; D011759:Pyrrolidines / Q000494:pharmacology; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water; D001616:beta-Galactosidase / Q000378:metabolism*; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D016227:Benzoquinones; D050113:Imino Furanoses; D047029:Lactams, Macrocyclic; D011759:Pyrrolidines; D011809:Quinones; D014867:Water; D008353:Mannitol; C043121:2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine; D001617:beta-Glucosidase; D001616:beta-Galactosidase; D007785:Lactose; D005690:Galactose; C001277:geldanamycin