Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates

Ho, Y. K.; Purohit, Atul; Vicker, Nigel; Newman, Simon P.; Robinson, James J.; Leese, Mathew P.; Ganeshapillai, Dharshini; Woo, L. W. Lawrence; Potter, Barry V. L.; Reed, Michael J.

doi:10.1016/s0006-291x(03)00865-9

Cited by 72 publications

(94 citation statements)

References 34 publications

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“…EMATE gives an IC 50 value of 2 nmol/L, although higher values of 9 and 42 nmol/L were reported previously (35,36). Compounds (2) and (10) are similar in potency, so the effect of a trifluoromethyl group on inhibitory activity is relatively small.…”

mentioning

confidence: 62%

Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography

Woo

Fischer

Sharland

et al. 2008

Molecular Cancer Therapeutics

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An improved steroid sulfatase inhibitor was prepared by replacing the N-propyl group of the second-generation steroid-like inhibitor (2) with a N-3,3,3-trifluoropropyl group to give (10). This compound is 5-fold more potent in vitro, completely inhibits rat liver steroid sulfatase activity after a single oral dose of 0.5 mg/kg, and exhibits a significantly longer duration of inhibition over (2). These biological properties are attributed to the increased lipophilicity and metabolic stability of (10) rendered by its trifluoropropyl group and also the potential H-bonding between its fluorine atom(s) and Arg 98 in the active site of human steroid sulfatase. Like other sulfamates, (10) is expected to be sequestered, and transported by, erythrocytes in vivo because it inhibits human carbonic anhydrase II (hCAII) potently (IC 50 , 3 nmol/L). A congener (4), which possesses a N-(pyridin-3-ylmethyl) substituent, is even more active (IC 50 , 0.1 nmol/L). To rationalize this, the hCAII-(4) adduct, obtained by cocrystallization, reveals not only the sulfamate group and the backbone of (4) interacting with the catalytic site and the associated hydrophobic pocket, respectively, but also the potential H-bonding between the N-(pyridin-3-ylmethyl) group and NE 2 of Gln 136 . Like (2), both (10) and its phenolic precursor (9) are non-estrogenic using a uterine weight gain assay. In summary, a highly potent, long-acting, and nonestrogenic steroid sulfatase inhibitor was designed with hCAII inhibitory properties that should positively influence in vivo behavior. Compound (10) and other related inhibitors of this structural class further expand the armory of steroid sulfatase inhibitors against hormone-dependent breast cancer. [Mol Cancer Ther 2008;7(8):2435 -44]

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mentioning

confidence: 62%

Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography

Woo

Fischer

Sharland

et al. 2008

Molecular Cancer Therapeutics

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“…Second, as we have previously shown that steroidal sulfamates bind to carbonic anhydrase II (CA II) in red blood cells in a reversible fashion, we reasoned that this may be a mechanism whereby they can be transported to tumours and released in the more acidic environment of the tumour. [59] Hence, a steroidal sulfamate that inhibits 17b-HSD1 may be delivered to the tumour bound to CA II and released at its site of action. Third, even if the sulfamates themselves are only weak 17b-HSD1 inhibitors, it is likely that steroid sulfatase will cleave the sulfamate group in vivo to some degree to release the corresponding phenols, which are potent 17b-HSD1 inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Vicker¹,

Lawrence²,

Allan³

et al. 2006

ChemMedChem

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17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented.

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“…The opposite direction of the genetic and pharmacological effects is intriguing, and could potentially be explained by the presence of compensatory processes in the gene deletion model which cannot occur in the case of acute enzyme inhibition. Differential behavioral effects in the genetic and pharmacological mouse models could also be explained by complete lack of the STS protein in the deletion model versus incomplete (~70%) inhibition of the enzyme in the pharmacological model (Nicolas et al., 2001), or by deletion of additional genes or genetic elements other than Sts in the genetic model (Trent et al., 2013; Trent, Fry, Ojarikre, & Davies, 2014) and possible off‐target effects in the pharmacological model (Ho et al., 2003). There is a growing body of evidence that pharmacological manipulation of the STS axis can influence the aspects of cognition and the underlying neural substrates (Yue et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

et al. 2017

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IntroductionThe enzyme steroid sulfatase (STS) converts sulfated steroids to their non‐sulfated forms. Deficiency for this enzyme is associated with inattention but preserved response control. The polymorphism rs17268988 within the X‐linked STS gene is associated with inattentive, but not other, symptoms in boys with attention deficit hyperactivity disorder (ADHD).MethodsWe initially tested whether rs17268988 genotype was associated with attention, response control, and underlying aspects of cognition, using questionnaires and neuropsychological tasks, in two independent cohorts of healthy adult males. In an additional analysis based upon existing data, the performance of mice with genetic or pharmacological manipulations of the STS axis under attentionally demanding conditions was investigated.ResultsG‐allele carriers at rs17268988 exhibited reduced reaction time, enhanced attention, and reduced reaction time variability relative to C‐allele carriers. Mice with genetic or pharmacological manipulations of the STS axis were shown to have perturbed reaction time variability.DiscussionOur findings provide additional support for an association between rs17268988 genotype and attention, which may be partially mediated by reaction time variability; they also indicate that, in contrast to the situation in boys with ADHD, in healthy men, the G‐allele at rs17268988 is associated with enhanced cognition. As reaction time variability is a predictor of well‐being, rs17268988 genotype may represent a biomarker for long‐term health.

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Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates

Cited by 72 publications

References 34 publications

Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography

Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

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