Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah, Mohamed; Abdelsamie, Ahmed S.; Frotscher, Martin

doi:10.1016/j.mce.2018.10.001

Cited by 29 publications

(36 citation statements)

References 112 publications

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“…Other pathways proteins. 17β-HSD2 is a microsomal enzyme that catalyzes the oxidation of sex steroids testosterone and estradiol (E2) to less active ketones androstenedione and estrone (E1) 85,86 . It is reported that the inhibition of 17β-HSD2 in a in vivo monkey model and osteoporosis patients is beneficial to increase in E2 and testosterone levels that facilitate reduction in bone resorption and maintenance of bone formation 87 .…”

Section: Discussionmentioning

confidence: 99%

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Tiwari

Mishra

Salemi

et al. 2020

Sci Rep

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Ibuprofen, an inhibitor of prostanoid biosynthesis, is a common pharmacological agent used for the management of pain, inflammation and fever. However, the chronic use of ibuprofen at high doses is associated with increased risk for cardiovascular, renal, gastrointestinal and liver injuries. The underlying mechanisms of ibuprofen-mediated effects on liver remain unclear. To determine the mechanisms and signaling pathways affected by ibuprofen (100 mg/kg/day for seven days), we performed proteomic profiling of male mice liver with quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) using ten-plex tandem mass tag (TMT) labeling. More than 300 proteins were significantly altered between the control and ibuprofen-treated groups. The data suggests that several major pathways including (1) energy metabolism, (2) protein degradation, (3) fatty acid metabolism and (4) antioxidant system are altered in livers from ibuprofen treated mice. Independent validation of protein changes in energy metabolism and the antioxidant system was carried out by Western blotting and showed sex-related differences. Proteasome and immunoproteasome activity/expression assays showed ibuprofen induced gender-specific proteasome and immunoproteasome dysfunction in liver. The study observed multifactorial gender-specific ibuprofen-mediated effects on mice liver and suggests that males and females are affected differently by ibuprofen. Ibuprofen, a propionic acid derivative, is the most common over-the-counter nonsteroidal anti-inflammatory (NSAID) drug used to treat fever, pain, inflammation and many other disorders 1. It has been included as a major medicine in the Essential Drugs List of the World Health Organization 2. Ibuprofen at low over-the-counter doses (800-1200 mg/day) is used to treat muscular aches, backaches, toothaches, and fever. At higher doses (1800-2400 mg/day), ibuprofen is prescribed for the treatment of chronic conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis 3. Ibuprofen is a non-selective inhibitor of the cyclo-oxygenase (COX) isozymes COX-1 and COX-2 that converts arachidonic acid into prostaglandins including thromboxane and prostacyclin 1. The anti-inflammatory, antipyretic and analgesic effects of ibuprofen are mediated through the inhibition of prostaglandins E2 (PGE2) and I2 (PGI2) production by blocking COX activity 1. Both PGE2 and PGI2 are pro-inflammatory prostanoids that increase vascular permeability, promote leukocyte infiltration and increase edema formation 4. The clearance of ibuprofen is mediated through oxidative metabolism by multiple cytochrome P450 (CYP) enzymes (CYP2C9, CYP2C8) to inactive primary metabolites including 3-hydroxy-ibuprofen, carboxy ibuprofen and 2-hydroxy-ibuprofen 5,6. Most of the ibuprofen is metabolized in liver, while only a small percentage of unchanged drug is excreted in the urine 5. The liver plays a key role in energy metabolism and is essential for whole body homeostasis via the regulation of glucose, lipid, and amino acid ...

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Section: Discussionmentioning

confidence: 99%

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Tiwari

Mishra

Salemi

et al. 2020

Sci Rep

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“…Further studies also established that 17β-HSD1 accomplished complex processes in ligand binding sites 11 , 28 . That is, the enzyme protein could change its conformation depending on the inhibitor molecule offered 12 .…”

Section: Resultsmentioning

confidence: 89%

“…These mechanisms indicate that a very small change in inhibitor structure can make large differences in the course of binding to the enzyme 12 . Inhibitor studies, therefore, may give ambiguous picture with regard to the binding properties of the compounds and complete structure–activity relations could be revealed sometimes scarcely 9 , 11 , 12 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1

Herman

Kiss

Wölfling

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of 17β-estradiol. Novel estrone-based compounds bearing various 15β-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17β-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC 50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17β-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.

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“…T here are studies which indicate that breast cancer is one of the main health problems worldwide [1][2][3][4]. It is noteworthy that some drugs have been used to treatment of breast cancer such as tamoxifen (estrogen-receptor antagonist) [5], anastrozole, letrozole or exemestane (aromatase inhibitors) [6][7][8], fisetin or methyl paraben (17-hydroxy dehydrogenase type 1 inhibitors) [9,10]; however, some of these drugs may produce some adverse effects such as secondary endometrial cancer [11] and bone loss [12]. In the search of new pharmacological treatment to breast cancer, some drugs have been developed; for example, the asymmetric synthesis of a piperidine derivative via an organocatalytic Michael-Henry reaction with biological activity against breast cancer in vitro [13].…”

Section: Introductionmentioning

confidence: 99%

Facile synthesis of two azete-steroid derivatives and theoretical evaluation of its interaction with the aromatase enzyme

Figueroa‐Valverde¹,

Díaz-Cedillo²,

Marcela³

et al. 2019

Hacettepe Journal of Biology and Chemistry

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M eme kanserinin tedavisi için birkaç aromataz inhibitörü kullanılmıştır; ancak, bu ilaçların bazıları endometrial kanser ve kemik kaybı gibi bazı yan etkiler yaratabilir. Bu çalışmanın amacı, bir yerleştirme modelinde kontroller olarak anastrozol ve exemestan kullanarak teorik etkileşimini bir aromataz enzimi (2wd3) ile teorik etkileşimini değerlendirmek için iki yeni azete-steroid türevini (bileşik 9 veya 10) sentezlemekti. 9 ve 10'un hazırlanması, aminasyon, eterleştirme, nitrasyon ve ekleme içeren bir dizi reaksiyon kullanılarak gerçekleştirildi. Bileşiklerin kimyasal yapısı element analizi ve NMR spektrumu kullanılarak doğrulandı. Sonuçlar, bileşikler 9 veya 10'un, anastrozol ve exemestan ile karşılaştırıldığında 2wd3 protein yüzeyinde yer alan farklı tipte bir amino asit tortusuna bağlanabileceğini gösterdi; bu fenomen, aromataz enziminin biyolojik aktivitesinde değişiklikler yapabilir. Tüm veriler, bileşik 9 veya 10'un, meme kanseri tedavisinde bir alternatif olabileceğini göstermektedir; bu nedenle ilaç endüstrisi için iyi bir aday olabilir.

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Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Cited by 29 publications

References 112 publications

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1

Facile synthesis of two azete-steroid derivatives and theoretical evaluation of its interaction with the aromatase enzyme

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