The Experts below are selected from a list of 1275 Experts worldwide ranked by ideXlab platform
Barry V L Potter - One of the best experts on this subject based on the ideXlab platform.
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c 3 and c 4 substituted bicyclic coumarin sulfamates as potent Steroid Sulfatase inhibitors
ACS Omega, 2018Co-Authors: Dharshini Ganeshapillai, Atul Purohit, Barry V L Potter, L Lawrence W Woo, Mark P. ThomasAbstract:Synthetic routes to potent bicyclic nonSteroidal sulfamate-based active-site-directed inhibitors of the enzyme Steroid Sulfatase (STS), an emerging target in the treatment of postmenopausal hormone...
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Design, synthesis, and biological evaluation of new arylamide derivatives possessing sulfonate or sulfamate moieties as Steroid Sulfatase enzyme inhibitors.
Bioorganic & medicinal chemistry, 2016Co-Authors: Mohammed I. El-gamal, Paul A. Foster, Mohammad H. Semreen, Barry V L PotterAbstract:A series of new arylamide derivatives possessing terminal sulfonate or sulfamate moieties was designed and synthesized. The target compounds were tested for in vitro inhibitory effects against the Steroid Sulfatase (STS) enzyme in a cell-free assay system. The free sulfamate derivative 1j was the most active. It inhibited the enzymatic activity by 72.0% and 55.7% at 20μM and 10μM, respectively. Compound 1j was further tested for STS inhibition in JEG-3 placental carcinoma cells with high STS enzyme activity. It inhibited 93.9% of the enzyme activity in JEG-3 placental carcinoma cells at 20μM with an efficacy near to that of the well-established drug STX64 as reference. At 10μM, 1j inhibited 86.1% of the STS activity of JEG-3. Its IC50 value against the STS enzyme in JEG-3 cells was 0.421μM. Thus, 1j represents an attractive new non-Steroidal lead for further optimization.
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Estrogen O-sulfamates and their analogues: Clinical Steroid Sulfatase inhibitors with broad potential.
The Journal of steroid biochemistry and molecular biology, 2015Co-Authors: Mark P. Thomas, Barry V L PotterAbstract:Estrogen sulfamate derivatives were the first irreversible active-site-directed inhibitors of Steroid Sulfatase (STS), an emerging drug target for endocrine therapy of hormone dependent diseases that catalyzes inter alia the hydrolysis of estrone sulfate to estrone. In recent years this has stimulated clinical investigation of the estradiol derivative both as an oral prodrug and its currently ongoing exploration in endometriosis. 2-Substituted Steroid sulfamate derivatives show considerable potential as multi-targeting agents for hormone-independent disease, but are also potent STS inhibitors. The Steroidal template has spawned nonSteroidal STS inhibitors one of which, Irosustat, has been evaluated clinically in breast cancer, endometrial cancer and prostate cancer and there is potential for innovative dual-targeting approaches. This review surveys the role of estrogen sulfamates, their analogues and current status.
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structure activity relationship for the first in class clinical Steroid Sulfatase inhibitor irosustat stx64 bn83495
ChemMedChem, 2011Co-Authors: L Lawrence W Woo, Atul Purohit, Mark P. Thomas, Oliver B. Sutcliffe, Mary F. Mahon, Dharshini Ganeshapillai, Bindu Malini, Barry V L PotterAbstract: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.
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Steroid Sulfatase a pivotal player in estrogen synthesis and metabolism
Molecular and Cellular Endocrinology, 2011Co-Authors: Atul Purohit, L Lawrence W Woo, Barry V L PotterAbstract:Steroid Sulfatase plays a pivotal role in regulating the formation of biologically active Steroids from inactive Steroid sulfates. It is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be subsequently reduced to Steroids with estrogenic properties (i.e. estradiol and androstenediol) that can stimulate the growth of tumors in hormone-responsive tissues of the breast, endometrium and prostate. Hence, the action of Steroid Sulfatase is implicated in physiological processes and pathological conditions. It has been five years since our group last reviewed the important role of this enzyme in Steroid synthesis and the progress made in the development of potent inhibitors of this important enzyme target. This timely review therefore concentrates on recent advances in Steroid Sulfatase research, and summarises the findings of clinical trials with Irosustat (BN83495), the only Steroid Sulfatase inhibitor that is being trialed in postmenopausal women with breast or endometrial cancer.
Donald Poirier - One of the best experts on this subject based on the ideXlab platform.
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AntiSulfatase, Osteogenic, and Anticancer Activities of Steroid Sulfatase Inhibitor EO-33 in Mice
2019Co-Authors: Donald Poirier, Jenny Roy, René Maltais, Diana AyanAbstract:Steroid Sulfatase (STS) is a key enzyme involved in the biosynthesis of estrogens from inactive sulfated Steroids. After we reported EO-33 as a potent in vitro STS inhibitor without undesirable estrogenic activity and with osteogenic properties, we are now interested in validating EO-33’s in vivo potential to inhibit STS, to prevent bone deterioration, and to reduce estrogen-dependent tumor growth. A scale-up synthesis was first elaborated to prepare the multigram quantity of EO-33 needed to perform in vivo studies. EO-33 blocked the uterine weight stimulated by estrone sulfate in ovariectomized mice by 69% and the STS activity in the liver by 81%. It also produced a selective estrogen receptor modulator effect as assessed by measuring the tibia weight and calcium content. Using a human breast cancer (MCF-7 xenograft) model in nude mice, EO-33 blocked 90% of tumor growth induced by estradiol sulfate, and no toxic effect was observed by assessing the body and liver weights
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discovery of a sulfamate based Steroid Sulfatase inhibitor with intrinsic selective estrogen receptor modulator properties
European Journal of Medicinal Chemistry, 2016Co-Authors: Rene Maltais, Charles Ouellet, Etienne Ouellet, Xavier Barbeau, Patrick Lague, Donald PoirierAbstract:Steroid Sulfatase (STS), the enzyme which converts inactive sulfated Steroid precursors into active hormones, is a promising therapeutic target for the treatment of estrogen-sensitive breast cancer. We report herein the synthesis and in vitro study of dual-action STS inhibitors with selective estrogen-receptor modulator (SERM) effects. A library of tetrahydroisoquinoline-N-substituted derivatives (phenolic compounds) was synthesized by solid-phase chemistry and tested on estrogen-sensitive breast cancer T-47D cells. Three phenolic compounds devoid of estrogenic activity and toxicity emerged from this screening. Their sulfamate analogs were then synthesized, tested in STS-transfected HEK-293 cells, and found to be potent inhibitors of the enzyme (IC50 of 3.9, 8.9, and 16.6 nM). When tested in T-47D cells they showed no estrogenic activity and produced a moderate antiestrogenic activity. The compounds were further tested on osteoblast-like Saos-2 cells and found to significantly stimulate their proliferation as well as their alkaline phosphatase activity, thus suggesting a SERM activity. These results are supported by molecular docking experiments.
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chemical synthesis and evaluation of 17α alkylated derivatives of estradiol as inhibitors of Steroid Sulfatase
ChemInform, 2012Co-Authors: Diane Fournier, Donald PoirierAbstract:Abstract Steroid Sulfatase (STS) controls the levels of 3-hydroxySteroids available from circulating Steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure–activity relationship study of this family of 17α-derivatives of E2.
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Steroid Sulfatase inhibitors a review covering the promising 2000 2010 decade
Steroids, 2011Co-Authors: Rene Maltais, Donald PoirierAbstract:Abstract The Steroid Sulfatase (STS) plays a major role in the regulation of Steroid hormone concentrations in several human tissues and target organs and therefore, represents an interesting target to regulate estrogen and androgen levels implicated in different diseases. In this review article, the emphasis is put on STS inhibitors reported in the fruitful 2000–2010 decade, which consolidated the first ones that were previously developed (1990–1999). The inhibitors reviewed are divided into four categories according to the fact that they are sulfamoylated or not or that they have a Steroid nucleus or not. Other topics such as function, localization, structure and mechanism as well as applications of STS inhibitors are also briefly discussed to complement the information on this crucial Steroidogenic enzyme and its inhibitors.
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estradiol dimers as a new class of Steroid Sulfatase reversible inhibitors
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Diane Fournier, Donald PoirierAbstract:A series of estradiol dimers was synthesized or selected from compounds available in our laboratory and tested for inhibition against Steroid Sulfatase. Dimers linked by their C17 position, compounds 7 and 8, showed inhibitory potency similar (56% and 54% at 1 microM) to that of our best previously reported reversible inhibitor EM-690 (62% at 1 microM). Docking experiment seems to indicate that C17-C17 dimers bind in a similar way to EM-690 whereas C16-O3 and C16-C16 dimers bind in an upside-down position.
Atul Purohit - One of the best experts on this subject based on the ideXlab platform.
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c 3 and c 4 substituted bicyclic coumarin sulfamates as potent Steroid Sulfatase inhibitors
ACS Omega, 2018Co-Authors: Dharshini Ganeshapillai, Atul Purohit, Barry V L Potter, L Lawrence W Woo, Mark P. ThomasAbstract:Synthetic routes to potent bicyclic nonSteroidal sulfamate-based active-site-directed inhibitors of the enzyme Steroid Sulfatase (STS), an emerging target in the treatment of postmenopausal hormone...
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Steroid Sulfatase inhibitors for estrogen and androgen dependent cancers
Journal of Endocrinology, 2012Co-Authors: Atul Purohit, Paul A. FosterAbstract:Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, Steroid Sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compoundsin vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novelinvivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.
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structure activity relationship for the first in class clinical Steroid Sulfatase inhibitor irosustat stx64 bn83495
ChemMedChem, 2011Co-Authors: L Lawrence W Woo, Atul Purohit, Mark P. Thomas, Oliver B. Sutcliffe, Mary F. Mahon, Dharshini Ganeshapillai, Bindu Malini, Barry V L PotterAbstract: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.
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Steroid Sulfatase a pivotal player in estrogen synthesis and metabolism
Molecular and Cellular Endocrinology, 2011Co-Authors: Atul Purohit, L Lawrence W Woo, Barry V L PotterAbstract:Steroid Sulfatase plays a pivotal role in regulating the formation of biologically active Steroids from inactive Steroid sulfates. It is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be subsequently reduced to Steroids with estrogenic properties (i.e. estradiol and androstenediol) that can stimulate the growth of tumors in hormone-responsive tissues of the breast, endometrium and prostate. Hence, the action of Steroid Sulfatase is implicated in physiological processes and pathological conditions. It has been five years since our group last reviewed the important role of this enzyme in Steroid synthesis and the progress made in the development of potent inhibitors of this important enzyme target. This timely review therefore concentrates on recent advances in Steroid Sulfatase research, and summarises the findings of clinical trials with Irosustat (BN83495), the only Steroid Sulfatase inhibitor that is being trialed in postmenopausal women with breast or endometrial cancer.
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development of Steroid Sulfatase inhibitors
Molecular and Cellular Endocrinology, 2011Co-Authors: L Lawrence W Woo, Atul Purohit, Barry V L PotterAbstract:Hydrolysis of biologically inactive Steroid sulfates to unconjugated Steroids by Steroid Sulfatase (STS) is strongly implicated in rendering estrogenic stimulation to hormone-dependent cancers such as those of the breast. Considerable progress has been made in the past two decades with regard to the discovery, design and development of STS inhibitors. We outline historical aspects of their development, cumulating in the discovery of the first clinical trial candidate STX64 (BN83495, Irosustat) and other sulfamate-based inhibitors. The development of reversible STS inhibitors and the design of dual inhibitors of both aromatase and STS is also discussed.
L Lawrence W Woo - One of the best experts on this subject based on the ideXlab platform.
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c 3 and c 4 substituted bicyclic coumarin sulfamates as potent Steroid Sulfatase inhibitors
ACS Omega, 2018Co-Authors: Dharshini Ganeshapillai, Atul Purohit, Barry V L Potter, L Lawrence W Woo, Mark P. ThomasAbstract:Synthetic routes to potent bicyclic nonSteroidal sulfamate-based active-site-directed inhibitors of the enzyme Steroid Sulfatase (STS), an emerging target in the treatment of postmenopausal hormone...
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structure activity relationship for the first in class clinical Steroid Sulfatase inhibitor irosustat stx64 bn83495
ChemMedChem, 2011Co-Authors: L Lawrence W Woo, Atul Purohit, Mark P. Thomas, Oliver B. Sutcliffe, Mary F. Mahon, Dharshini Ganeshapillai, Bindu Malini, Barry V L PotterAbstract: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.
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Steroid Sulfatase a pivotal player in estrogen synthesis and metabolism
Molecular and Cellular Endocrinology, 2011Co-Authors: Atul Purohit, L Lawrence W Woo, Barry V L PotterAbstract:Steroid Sulfatase plays a pivotal role in regulating the formation of biologically active Steroids from inactive Steroid sulfates. It is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be subsequently reduced to Steroids with estrogenic properties (i.e. estradiol and androstenediol) that can stimulate the growth of tumors in hormone-responsive tissues of the breast, endometrium and prostate. Hence, the action of Steroid Sulfatase is implicated in physiological processes and pathological conditions. It has been five years since our group last reviewed the important role of this enzyme in Steroid synthesis and the progress made in the development of potent inhibitors of this important enzyme target. This timely review therefore concentrates on recent advances in Steroid Sulfatase research, and summarises the findings of clinical trials with Irosustat (BN83495), the only Steroid Sulfatase inhibitor that is being trialed in postmenopausal women with breast or endometrial cancer.
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development of Steroid Sulfatase inhibitors
Molecular and Cellular Endocrinology, 2011Co-Authors: L Lawrence W Woo, Atul Purohit, Barry V L PotterAbstract:Hydrolysis of biologically inactive Steroid sulfates to unconjugated Steroids by Steroid Sulfatase (STS) is strongly implicated in rendering estrogenic stimulation to hormone-dependent cancers such as those of the breast. Considerable progress has been made in the past two decades with regard to the discovery, design and development of STS inhibitors. We outline historical aspects of their development, cumulating in the discovery of the first clinical trial candidate STX64 (BN83495, Irosustat) and other sulfamate-based inhibitors. The development of reversible STS inhibitors and the design of dual inhibitors of both aromatase and STS is also discussed.
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hybrid dual aromatase Steroid Sulfatase inhibitors with exquisite picomolar inhibitory activity
ACS Medicinal Chemistry Letters, 2011Co-Authors: L Lawrence W Woo, Atul Purohit, Christian Bubert, Barry V L PotterAbstract:Single agents against multiple drug targets are highly topical. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and Steroid Sulfatase (STS), and several dual aromatase-Sulfatase inhibitors (DASIs) have been recently reported. The best compounds from two leading classes of DASI, 3 and 9, are low nanomolar inhibitors. In search of a novel class of DASI, core motifs of two leading classes were combined to give a series of hybrid structures, with several compounds showing markedly improved dual inhibitory activities in the picomolar range in JEG-3 cells. Thus, DASIs 14 (IC50: aromatase, 15 pM; STS, 830 pM) and 15 (IC50: aromatase, 18 pM; STS, 130 pM) are the first examples of an exceptional new class of highly potent dual inhibitor that should encourage further development toward multitargeted therapeutic intervention in HDBC.
Andreas Billich - One of the best experts on this subject based on the ideXlab platform.
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estrone formate a novel type of irreversible inhibitor of human Steroid Sulfatase
ChemInform, 2005Co-Authors: Erwin P Schreiner, Andreas BillichAbstract:Abstract A series of estrone conjugates of the type estrone-3-O-C(O,S)-X have been prepared and evaluated for inhibition of human Steroid Sulfatase (STS). Among the carbamate (6), thiocarbamate (8), cyanate (7), formate (9), and acetate (10) analogs of estrone, only 9 was found to inhibit STS in a time- and concentration-dependent manner. With an IC50 of 0.42 μM 9 is the first potent inactivator of STS which does not feature the sulfamate group. Furthermore a formate-type inhibitor featuring a benzoxazole moiety in place of the Steroid skeleton (14) was prepared, suggesting a general principle of inactivation by the formate group. As the mode of action we propose an immediate transfer of the formyl moiety to a nucleophilic residue in the active site of STS.
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Steroid Sulfatase inhibitors
ChemInform, 2004Co-Authors: Peter Nussbaumer, Andreas BillichAbstract:Steroid Sulfatase (STS) regulates the local production of estrogens and androgens from systemic precursors in several tissues. The enzyme catalyzes the hydrolysis of the sulfate esters of 3-hydroxy Steroids, which are inactive transport or precursor forms of the active 3-hydroxy Steroids. STS inhibitors are expected to block the local production and, consequently, to reduce the local levels of the hormones. Therefore, they are considered as potential new therapeutic agents for the treatment of estrogen- and androgen-dependent disorders. Indications range from cancers of the breast, endometrium and prostate to androgenetic alopecia and acne. In this review, we give a comprehensive summary of the current knowledge and problems in the field of medicinal chemistry of STS inhibitors. The various types of inhibitors are presented and their structure-activity relationships are discussed. In addition to potent arylsulfamate-based, irreversible inhibitors, novel types of reversible inhibitors were recently discovered. The recent publication of the X-ray structure of STS will further boost research activities on this attractive target.
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2 1 adamantyl 4 thio chromenone 6 carboxylic acids potent reversible inhibitors of human Steroid Sulfatase
Journal of Medicinal Chemistry, 2004Co-Authors: Horvath Amarylla, Peter Nussbaumer, Barbara Wolff, Andreas BillichAbstract:Steroid Sulfatase (STS) is an attractive target for the potential therapy of a number of estrogen- and androgen-dependent disorders. Most potent STS inhibitors known so far act as irreversible enzyme blockers and feature an aryl sulfamate moiety; even minor modifications at the sulfamate group result in drastically decreased activity. On the basis of a recently reported subclass of highly potent STS inhibitors, i.e., chromenone sulfamates, we now extended the investigation of structure-activity relationships to hitherto unstudied sulfamate replacements. Thereby, we discovered 2-(1-adamantyl)-4-(thio)chromenone-6-carboxylic acids (5d and 5j) as potent, reversible inhibitors of STS. In a cell-free system using purified human STS, both new inhibitors show similar Ki values (0.50 microM and 0.53 microM, respectively). However, the thio analogue 5j is superior to 5d (IC50 = 0.18 microM versus 9.4 microM) in a cellular assay system using CHO cells overexpressing STS. Compound 5j is an example of a reversible STS inhibitor with potent activity toward the target enzyme in a cellular test system. Moreover, 5d,j are stable and have no estrogenic potential.
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nortropinyl arylsulfonylureas as novel reversible inhibitors of human Steroid Sulfatase
ChemInform, 2004Co-Authors: Peter Nussbaumer, Philipp Lehr, Barbara Wolff, Geyl Dieter, Horvath Amarylla, Andreas BillichAbstract:Steroid Sulfatase (STS) has emerged as an attractive target for a range of estrogen- and androgen-dependent diseases. Searching for novel chemotypes as STS inhibitors, we identified nortropinyl-arylsulfonylurea 3 as a hit from high-throughput screening. A series of analogues was prepared in order to explore the essential structural elements for STS inhibition, and first structure-activity relationships were established. Mechanistic investigations revealed that the compounds are reversible, competitive inhibitors of STS.
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6 2 adamantan 2 ylidene hydroxybenzoxazole o sulfamate a potent non Steroidal irreversible inhibitor of human Steroid Sulfatase
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Erwin P Schreiner, Barbara Wolff, Anthony Winiski, Andreas BillichAbstract:We report the synthesis and results from the in vitro evaluation of 6-(adamantan-2-ylidene-hydroxybenzoxazole)-O-sulfamate 1 as an irreversible inhibitor of human Steroid Sulfatase (STS). Highly straightforward, condensation of 2-methyl-6-hydroxybenzoxazole with 2-adamantanone, subsequent elimination of water and sulfamoylation provide the title compound in 45% overall yield from the inexpensive 2,4-dihydroxyacetophenone. 1 was found to be a potent irreversible inhibitor of purified human Steroid Sulfatase (STS) and specific for this enzyme relative to human arylSulfatases A and B. In cellular assays with human keratinocytes, sebocytes and fibroblasts, 1 blocked STS activity with IC(50) values in the range of 0.15-0.8 nM, and in MCF-7 breast cancer cells with IC(50)=2.3 nM, while it did not bind to estrogen receptors alpha and beta. Thus, 1 is a candidate for further investigation of its potential as a drug to be used in androgen- and estrogen-dependent diseases.