Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1500-1508. doi: 10.1080/14756366.2021.1937142.

Abstract

Enzymes AKR1C regulate the action of oestrogens, androgens, and progesterone at the pre-receptor level and are also associated with chemo-resistance. The activities of these oestrone halides were investigated on recombinant AKR1C enzymes. The oestrone halides with halogen atoms at both C-2 and C-4 positions (13β-, 13α-methyl-17-keto halogen derivatives) were the most potent inhibitors of AKR1C1. The lowest IC50 values were for the 13α-epimers 2_2I,4Br and 2_2I,4Cl (IC50, 0.7 μM, 0.8 μM, respectively), both of which selectively inhibited the AKR1C1 isoform. The 13α-methyl-17-keto halogen derivatives 2_2Br and 2_4Cl were the most potent inhibitors of AKR1C2 (IC50, 1.5 μM, 1.8 μM, respectively), with high selectivity for the AKR1C2 isoform. Compound 1_2Cl,4Cl showed the best AKR1C3 inhibition, and it also inhibited AKR1C1 (Ki: AKR1C1, 0.69 μM; AKR1C3, 1.43 μM). These data show that halogenated derivatives of oestrone represent a new class of potent and selective AKR1C inhibitors as lead compounds for further optimisations.

Keywords: Aldo-keto reductase; halogenated oestrone derivatives; inhibition; structure–activity relationships.

MeSH terms

  • 20-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 20-Hydroxysteroid Dehydrogenases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Estrone / analogs & derivatives
  • Estrone / chemistry
  • Estrone / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Estrone
  • 20-Hydroxysteroid Dehydrogenases
  • 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase

Grants and funding

The work of Erzsébet Mernyák on this project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. This work was supported by the National Research, Development and Innovation Office-NKFIH through project OTKA SNN 124329 and project N1-0066 from the Slovenian Research Agency.