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Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors.

European journal of medicinal chemistry (2015-07-15)
Sebastian Demkowicz, Witold Kozak, Mateusz Daśko, Maciej Masłyk, Bartłomiej Gielniewski, Janusz Rachon
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Potassium carbonate, 99.995% trace metals basis
Sigma-Aldrich
Potassium carbonate, anhydrous, powder, 99.99% trace metals basis
Sigma-Aldrich
Thiophosphoryl chloride, 98%
Sigma-Aldrich
Potassium carbonate, meets USP testing specifications
Sigma-Aldrich
Potassium carbonate, BioUltra, anhydrous, ≥99.0% (T)