Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)

Chem Biol Interact. 2015 Jun 5;234:339-48. doi: 10.1016/j.cbi.2014.12.015. Epub 2014 Dec 31.


Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.

Keywords: Androgen; Androgen receptor signaling; Castration resistant prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • Aldo-Keto Reductase Family 1 Member C3
  • Cinnamates / metabolism
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors*
  • Hydroxysteroid Dehydrogenases / antagonists & inhibitors
  • Structure-Activity Relationship
  • Trichothecenes / pharmacology*


  • Cinnamates
  • Trichothecenes
  • cinnamic acid
  • baccharin
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxysteroid Dehydrogenases
  • Hydroxyprostaglandin Dehydrogenases
  • AKR1C2 protein, human
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3