irosustat and sulfamic-acid

Steroid sulfatase (STS) plays a momentous role in the conversion of sulfated steroids, which are biologically inactive, into biologically active un-sulfated steroid hormones, which support the development and growth of a number of hormone-dependent cancers, including breast cancer. Therefore, inhibitors of STS are supposed to be potential drugs for the treatment of breast and other steroid-dependent cancers. The present review concentrates on broad chemical classification of steroid sulfatase inhibitors. The inhibitors reviewed are classified into four main categories: Steroid sulfamate based inhibitors; Steroid non-sulfamate based inhibitors; Non-steroidal sulfamate based inhibitors; Non-steroidal non-sulfamate based inhibitors. A succinct overview of current treatment of cancer, estradiol precursors, STS enzyme and its role in breast cancer is herein described.

Topics: Breast Neoplasms; Enzyme Inhibitors; Estrogens; Female; Humans; Neoplasm Recurrence, Local; Sulfatases; Sulfonic Acids

Steroid sulfatase (STS) has recently emerged as a drug target for management of hormone-dependent malignancies. In the present study, a new series of twenty-one aryl amido-linked sulfamate derivatives 1a-u was designed and synthesized, based upon a cyclohexyl lead compound. All members were evaluated as STS inhibitors in a cell-free assay. Adamantyl derivatives 1h and 1p-r were the most active with more than 90% inhibition at 10 µM concentration and, for those with the greatest inhibitory activity, IC

Topics: Antineoplastic Agents; Breast Neoplasms; Cell-Free System; Female; Humans; Inhibitory Concentration 50; Molecular Structure; Steryl-Sulfatase; Structure-Activity Relationship; Sulfonic Acids

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.

Topics: Acrylamides; Cell Line, Tumor; Enzyme Inhibitors; Female; Humans; Placenta; Pregnancy; Steryl-Sulfatase; Sulfonic Acids

In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some 20 years, have led to steroidal and nonsteroidal drugs in numerous preclinical and clinical trials, with promising results in oncology and women's health, including endometriosis. Drugs have been designed to inhibit STS, e.g., Irosustat, as innovative dual-targeting aromatase-steroid sulfatase inhibitors (DASIs) and as multitargeting agents for hormone-independent tumors, such as the steroidal STX140 and nonsteroidal counterparts, acting inter alia through microtubule disruption. The aryl sulfamate pharmacophore is highly versatile, operating via three distinct mechanisms of action, and imbues attractive pharmaceutical properties. This Perspective gives a personal view of the work leading both to the therapeutic concepts and these drugs, their current status, and how they might develop in the future.

Topics: Animals; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Drug Discovery; Endometriosis; Estrone; Female; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Steryl-Sulfatase; Sulfonic Acids; Tubulin Modulators

The hydrolysis of N-methyl O-phenyl sulfamate (1) has been studied as a model for steroid sulfatase inhibitors such as Coumate, 667 Coumate, and EMATE. At neutral pH, simulating physiological conditions, hydrolysis of 1 involves an intramolecular proton transfer from nitrogen to the bridging oxygen atom of the leaving group. Remarkably, this proton transfer is estimated to accelerate the decomposition of 1 by a factor of 10(11). Examination of existing kinetic data reveals that the sulfatase PaAstA catalyzes the hydrolysis of sulfamate esters with catalytic rate accelerations of ~10(4), whereas the catalytic rate acceleration generated by the enzyme for its cognate substrate is on the order of ~10(15). Rate constants for hydrolysis of a wide range of sulfuryl esters, ArOSO(2)X(-), are shown to be correlated by a two-parameter equation based on pK(a)(ArOH) and pK(a)(ArOSO2XH).

Topics: Arylsulfatases; Catalysis; Coumarins; Esters; Estrone; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Molecular Structure; Steryl-Sulfatase; Sulfonamides; Sulfonic Acids

In our search for potent inhibitors of the enzyme estrone sulfatase (ES), we have undertaken the synthesis and biochemical evaluation of a range of esters of 4-[(aminosulfonyl)oxy] benzoic acid. The results of the study show that the synthesised compounds possess potent inhibitory activity, indeed the cyclooctyl derivative was found to be more potent than 667-COUMATE, which is currently undergoing clinical trials.

Topics: Antineoplastic Agents; Benzoic Acid; Coumarins; Enzyme Inhibitors; Esters; Inhibitory Concentration 50; Structure-Activity Relationship; Sulfatases; Sulfonamides; Sulfonic Acids

Oestrogen sulphamates have increased systemic, but reduced hepatic oestrogenicity which results from their sequestration and transport through the liver by red blood cells. Oestrogen sulphamates act as prodrugs for the release of natural oestrogens but, as yet, there is little information as to how the sulphamoyl moiety is cleaved from the steroid nucleus. In the present investigation we have used the potent steroid sulphatase (STS) inhibitor, 667 COUMATE, to explore the possibility that STS might be responsible for the hydrolysis of oestrogen sulphamates. Administration of oestrone sulphamate (10 microg/day, s.c., for 5 days) to ovariectomised rats resulted in a 3.5-fold increase in the uterine weights of treated animals. Co-administration of oestrone sulphamate and 667 COUMATE (2 mg/kg) completely blocked STS activity in treated animals and completely abrogated the ability of oestrone sulphamate to stimulate uterine growth. In vitro studies, using [(3)H]oestrone sulphamate or [(3)H]oestrone, revealed that the uptake of the sulphamate derivative (95.9+/-2.4%) by red blood cells was considerably higher than that for the non-sulphamoylated oestrogen (25.1+/-1.9%). Results from these studies demonstrate convincingly that STS is the enzyme responsible for the removal of the sulphamoyl group from oestrogen sulphamates. This enzyme therefore has a crucial role in regulating the oestrogenicity associated with this class of drug.

Topics: Animals; Coumarins; Drug Combinations; Estrogens; Estrone; Female; Homeostasis; Organ Size; Ovariectomy; Rats; Rats, Wistar; Steryl-Sulfatase; Sulfonamides; Sulfonic Acids; Uterus

The development of inhibitors to block the formation of estrone and 5-androstenediol from sulfated precursors is an important new strategy for the treatment of breast cancer. In this study a series of tricyclic coumarin sulfamates (665-668 COUMATE) and a tricyclic oxepin sulfamate have been synthesised and tested for their ability to inhibit estrone sulfatase activity (E1-STS). In addition the effect of the steroid-based E1-STS inhibitor, 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE) on the morphology of MDA-MB-231 cells and breast tumour-derived fibroblasts was also examined. The tricyclic coumarin sulfamates and oxepin sulfamate were potent inhibitors of E1-STS activity with IC(50)s ranging from 8 to 250 nM. Of this series 667 COUMATE was the most potent inhibitor (IC(50)=8 nM) and was three-times more potent than estrone-3-O-sulfamate (EMATE, IC(50)=25 nM). 667 COUMATE did not stimulate the growth of MCF-7 breast cancer cells and is therefore devoid of estrogenicity. In vivo, 667 COUMATE inhibited E1-STS activity in rat liver tissue to a similar extent to that of EMATE. 2-MeOEMATE had a marked effect on the morphology of MDA-MB-231 cells and breast tumour-derived fibroblasts causing a significant increase in the number of rounded cells. 667 COUMATE and 2-MeOEMATE therefore offer considerable potential for development for cancer therapy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Coumarins; Enzyme Inhibitors; Estrogens; Estrone; Female; Humans; Kinetics; Oxepins; Rats; Rats, Wistar; Sulfatases; Sulfonamides; Sulfonic Acids; Tumor Cells, Cultured