Structure-activity relationship for the first-in-class clinical steroid sulfatase inhibitor Irosustat (STX64, BN83495).

L W Lawrence Woo,Bindu Malini,Atul Purohit,Dharshini Ganeshapillai,Mary F Mahon,Mark P Thomas,Barry V L Potter,Oliver B Sutcliffe

doi:10.1002/cmdc.201100288

L W Lawrence Woo, Bindu Malini + Show 6 more

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https://doi.org/10.1002/cmdc.201100288

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Abstract

Structure–activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors in vitro had IC50 values between 0.015 and 0.025 nm. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine 75 during the inactivation mechanism.

Highlights

The inhibition of steroid sulfatase (STS) as a new target for endocrine therapy has attracted considerable attention over the past two decades after recognition that the STS pathway could be a significant source of oestrogens alongside those originating from aromatase, the enzyme that aromatises androgens to oestrogens
With the exception of ethyl 2-oxocyclotridecanecarboxylate, which is available commercially, the starting cyclic b-keto esters required for the synthesis of tricyclic coumarins 6 b–9 b and 11 b were prepared by treating the corresponding cycloalkyl ketone with diethyl carbonate in the presence of two equivalents of sodium hydride at room temperature.[18]
The most potent compounds observed are 6–8, the IC50 values of which are between 0.015 and 0.025 nm, whereas 11 is the weakest STS inhibitor in vitro. These results suggest that the ability of compounds to cross the cell membrane and to interact with the active site of STS is optimal with compounds 6–8, when the aliphatic ring contains 8–10 carbon atoms

Summary

Introduction

The inhibition of steroid sulfatase (STS) as a new target for endocrine therapy has attracted considerable attention over the past two decades after recognition that the STS pathway could be a significant source of oestrogens alongside those originating from aromatase, the enzyme that aromatises androgens to oestrogens Evidence to support this hypothesis includes: 1) a millionfold higher STS activity than aromatase activity in liver as well as normal and malignant breast tissues,[1] 2) the origin of oestrone (E1) from oestrone sulfate (E1S) in breast cancer tissue is ~ 10-fold greater than that from androstenedione,[2] and 3) STS expression is an important prognostic factor in human breast carcinoma.[3,4] Most oestrogens that originate from the aromatase pathway are converted into and stored in the body as sulfate conjugates that per se are biologically inactive.

Results and Discussion

78 Æ 13 283 Æ 66

Conclusions