Abstract
A novel 17-allylamino-17-demethoxygeldanamycin (17-AAG) glucoside (1) was obtained from in vitro enzymatic glycosylation using a UDP-glycosyltransferase (YjiC). The water-solubility of compound 1 was approximately 10.5 times higher than that of the substrate, 17-AAG. Compound 1 showed potential anti-proliferative activities against five human cancer cell lines, with IC50 values ranging from 5.26 to 28.52 μM. Further studies also indicated that compound 1 could inhibit the growth of CNE-2Z cells by inducing the degradation of Hsp90 client proteins (Akt, c-Raf, Bcl-2, and HIF-1α). In addition, compound 1 showed greater potential anti-tumor efficacy than 17-AAG in nude mice xenografted with CNE-2Z cells. Therefore, we suggest that in vitro enzymatic glycosylation is a powerful approach for the structural optimization of 17-AAG.
Keywords:
17-AAG; Anti-cancer; Glycosylation; Hsp90; Water-solubility.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Benzoquinones / chemistry
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Benzoquinones / metabolism
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Benzoquinones / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Glucosides / biosynthesis
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Glucosides / chemistry
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Glucosides / pharmacology*
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Glycosylation
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Glycosyltransferases / metabolism*
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Humans
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / metabolism
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Lactams, Macrocyclic / pharmacology*
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Mice
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Mice, Nude
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Structure-Activity Relationship
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Uridine Diphosphate / metabolism*
Substances
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Antineoplastic Agents
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Benzoquinones
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Glucosides
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Lactams, Macrocyclic
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tanespimycin
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Uridine Diphosphate
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Glycosyltransferases