C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

Ganeshapillai, Dharshini; Woo, L. W. Lawrence; Thomas, Mark; Purohit, Atul; Potter, Barry V. L.

doi:10.1021/acsomega.8b01383

Cited by 21 publications

(16 citation statements)

References 72 publications

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“…Hence, STS represents a central target for anti-cancer drug development. The STS inhibitor irosustat promisingly passed phase II clinical trials (5), and further drug development efforts are ongoing (194,195).…”

Section: Potential Applicationsmentioning

confidence: 99%

Sulfation pathways from red to green

Günal

Hardman

Kopriva

et al. 2019

Journal of Biological Chemistry

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Edited by Joseph M. JezSulfur is present in the amino acids cysteine and methionine and in a large range of essential coenzymes and cofactors and is therefore essential for all organisms. It is also a constituent of sulfate esters in proteins, carbohydrates, and numerous cellular metabolites. The sulfation and desulfation reactions modifying a variety of different substrates are commonly known as sulfation pathways. Although relatively little is known about the function of most sulfated metabolites, the synthesis of activated sulfate used in sulfation pathways is essential in both animal and plant kingdoms. In humans, mutations in the genes encoding the sulfation pathway enzymes underlie a number of developmental aberrations, and in flies and worms, their loss-of-function is fatal. In plants, a lower capacity for synthesizing activated sulfate for sulfation reactions results in dwarfism, and a complete loss of activated sulfate synthesis is also lethal. Here, we review the similarities and differences in sulfation pathways and associated processes in animals and plants, and we point out how they diverge from bacteria and yeast. We highlight the open questions concerning localization, regulation, and importance of sulfation pathways in both kingdoms and the ways in which findings from these "red" and "green" experimental systems may help reciprocally address questions specific to each of the systems.Sulfur (S) is an essential nutrient for all life forms. It is present in a plethora of metabolites of primary and secondary metabolism, most prominently in the amino acids cysteine and methionine, and cofactors such as iron-sulfur clusters, lipoic acid, and CoA. In the majority of these metabolites, sulfur is present in its reduced form of organic thiols; however, some compounds contain S in its oxidized form of sulfate (1, 2). Sulfate is transferred to suitable substrates onto hydroxyl or amino groups by sulfotransferases (3,4). These biological sulfation reactions as well as desulfation catalyzed by sulfatases are often denoted as sulfation pathways (Fig. 1) (5, 6).The activated sulfate for the sulfation pathways, 3Ј-phosphoadenosine 5-phosphosulfate (PAPS), 3 is formed from sulfate by two ATP-dependent steps: adenylation, i.e. the transfer of the AMP moiety of ATP to sulfate to form adenosine 5Ј-phosphosulfate (APS) by ATP sulfurylase (ATPS), and the phosphorylation of APS at its 3Ј-OH group by APS kinase. The two enzymes are either fused into a single enzyme PAPS synthase (PAPSS) in the animal kingdom or occur as independent proteins in the green lineage (7). The by-product of PAPS-dependent sulfation reactions, 3Ј-phosphoadenosine 5-phosphate (PAP), is finally dephosphorylated to AMP by 3Ј-nucleotidases. This reaction to remove PAP is important beyond the sulfation pathways, as PAP accumulation has many additional physiological effects (8,9). Sulfate activation to APS or PAPS is a prerequisite not only for sulfation pathways but also for primary sulfate assimilation in plants, algae, bacteria, and fungi (2). Parti...

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Section: Potential Applicationsmentioning

confidence: 99%

Sulfation pathways from red to green

Günal

Hardman

Kopriva

et al. 2019

Journal of Biological Chemistry

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“…The synthesis of sulphamoylated coumarin derivatives is still one of the main directions in the development of compounds with STS inhibitory activities. Ganeshapillai et al 59 synthesised a series of novel STS inhibitors based on bicyclic coumarin sulphamates. Based on the chemical structure of COUMATE, a large library of C-3-and C-4-substituted derivatives containing a sulphamate moiety was obtained and a wide SAR analysis was performed.…”

Section: Nonsteroidal Sts Inhibitors Containing a Sulphamate Moietymentioning

confidence: 99%

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

Daśko

Demkowicz

Biernacki

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The purpose of this review article is to provide an overview of recent achievements in the synthesis of novel steroid sulphatase (STS) inhibitors. STS is a crucial enzyme in the biosynthesis of active hormones (including oestrogens and androgens) and, therefore, represents an extremely attractive molecular target for the development of hormone-dependent cancer therapies. The inhibition of STS may effectively reduce the availability of active hormones for cancer cells, causing a positive therapeutic effect. Herein, we report examples of novel STS inhibitors based on steroidal and nonsteroidal cores that contain various functional groups (e.g. sulphamate and phosphorus moieties) and halogen atoms, which may potentially be used in therapies for hormone-dependent cancers. The presented work also includes examples of multitargeting agents with STS inhibitory activities. Furthermore, the fundamental discoveries in the development of the most promising drug candidates exhibiting STS inhibitory activities are highlighted.

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“…Thus, inhibition of STS represents an attractive avenue for treatment of those hormone-dependent cancers [1,2]. Numerous molecules possessing the unsubstituted sulfamate moiety have been reported and developed as STS inhibitors [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. An aryl sulfamate moiety is essential for potent inhibition [3,5].…”

Section: Introductionmentioning

confidence: 99%

A new series of aryl sulfamate derivatives: Design, synthesis, and biological evaluation

El‐Gamal

Zaraei

Foster

et al. 2020

Bioorganic & Medicinal Chemistry

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C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

Cited by 21 publications

References 72 publications

Sulfation pathways from red to green

Sulfation pathways from red to green

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

A new series of aryl sulfamate derivatives: Design, synthesis, and biological evaluation

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