Synthesis and biological evaluation of thiophosphate tricyclic coumarin derivatives as steroid sulfatase inhibitors

Abstract

Steroid sulfatase (STS) enzyme inhibition is an important approach to the management of hormone-dependent breast cancer. In this paper, we report convenient methods for the synthesis and biological evaluation of thiophosphate tricyclic coumarin analogs exhibiting STS activity. The described methods are based on the straightforward preparation of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-2-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 and their further modification by the introduction of various thiophosphate moieties. The inhibition properties of the synthesized compounds were tested toward STS isolated from human placenta. Most of the new STS inhibitors possessed good to moderate activity toward STS. During the course of our investigation, the largest inhibitory effects in the STS enzyme assays were observed for the two compounds 3f and 4r, with IC50 values of 13.3 and 30.3 μM, respectively (the IC50 value of 1 μM for the 665-COUMATE was used as a reference). The structure-activity relationships of the synthesized coumarin derivatives toward STS enzymes are discussed.

Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade

“…Although the mechanism of inhibition is unknown, docking studies suggest the possibility of a phosphate group transfer to fGly75 during the inactivation process. Further development led to the synthesis of thiophosphate analogues with slightly improved inhibitory potencies 79 . The highest activity (in an assay with an isolated enzyme) was exhibited by compound 34 (Table 3), which contained a chlorothiophosphate group (IC 50 value of 13.3 mM).…”

Selected organophosphorus compounds with biological activity. Applications in medicine

“…42 The initial strategy employed for generating a lead STS inhibitor involved replacement of the sulfate group (OSO 3 ) on the natural enzyme substrate with surrogates or mimics such as phosphates or thiophosphates. Recently, Demkowicz et al synthesized new phosphate and thiophosphate esters of tricyclic coumarin 39, 43,44 N-alkanoyl tyramine 40, 45 49 The clinical trial ndings revealed that the drug can selectively inhibit cell proliferation and induce tumor cell apoptosis through the farnesoid X receptor. In vitro assay results showed that 63 and 91% of ovarian cancers were sensitive to apomine at concentrations of 10 and 20 mM, respectively.…”

Development of Sulfamoylated 4-(1-Phenyl-1H-1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer

“…Irosustat demonstrated a very potent STS inhibitory effect (IC 50 value of 8 nM) with no in vivo and in vitro estrogenic properties. Irosustat resulted to be orally active and, as such, reached clinical trials, − showing great therapeutic potential in several clinical studies. − To date, other coumarin derivatives with sulfamate, phosphate, , and thiophosphate − moieties as well as fluorinated compounds , have been reported as potent STS inhibitors.…”