Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors

Eur J Med Chem. 2015 Aug 28:101:358-66. doi: 10.1016/j.ejmech.2015.06.051. Epub 2015 Jul 2.

Abstract

Based on the frameworks of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-4-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one, a series of bicoumarin thiophosphate analogs have been synthesized and biologically evaluated. Additionally, their binding modes have been modeled using docking techniques. The inhibitory properties of the synthesized compounds were tested against the STS isolated from human placenta. Most of the new STS inhibitors possessed good activities against STS. In particular, we found that the bis-(6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yl) hydrogenthiophosphate (10b) produced the largest inhibitory effect, with an IC50 value of 860 nM (an IC50 value of 1 μM for the 665-COUMATE used as a reference). The structure-activity relationships of the synthesized bicoumarin thiophosphate derivatives toward the STS enzyme have been discussed previously.

Keywords: Bicoumarin thiophosphates; Breast cancer; Molecular docking; STS inhibitors; Steroid sulfatase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Coumarins / chemical synthesis
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Organothiophosphates / chemical synthesis
  • Organothiophosphates / chemistry
  • Organothiophosphates / pharmacology*
  • Steryl-Sulfatase / antagonists & inhibitors*
  • Steryl-Sulfatase / metabolism
  • Structure-Activity Relationship

Substances

  • Coumarins
  • Enzyme Inhibitors
  • Organothiophosphates
  • bis(6-oxo-7,8,9,10-tetrahydro-6H-benzo(c)chromen-3-yl) hydrogen thiophosphate
  • Steryl-Sulfatase