Enzymatic biosynthesis and biological evaluation of novel 17-AAG glucoside as potential anti-cancer agents

Bioorg Med Chem Lett. 2020 Aug 1;30(15):127282. doi: 10.1016/j.bmcl.2020.127282. Epub 2020 May 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzoquinones / chemistry
  • Benzoquinones / metabolism
  • Benzoquinones / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Glucosides / biosynthesis
  • Glucosides / chemistry
  • Glucosides / pharmacology*
  • Glycosylation
  • Glycosyltransferases / metabolism*
  • Humans
  • Lactams, Macrocyclic / chemistry
  • Lactams, Macrocyclic / metabolism
  • Lactams, Macrocyclic / pharmacology*
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Structure-Activity Relationship
  • Uridine Diphosphate / metabolism*

Substances

  • Antineoplastic Agents
  • Benzoquinones
  • Glucosides
  • Lactams, Macrocyclic
  • tanespimycin
  • Uridine Diphosphate
  • Glycosyltransferases