Hydrogen bonding in steroidogenesis: Studies on new heterocyclic analogs of estrone that inhibit human estradiol 17β-dehydrogenase

Sweet, Frederick; Boyd, James; Medina, Olga; Konderski, Lech; Murdock, Gary L.

doi:10.1016/s0006-291x(05)81173-8

Cited by 28 publications

(23 citation statements)

References 19 publications

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“…C16,C17-substituted pyrazole and isoxazole E 1 derivatives (Fig. 3d) have also been shown to be competitive inhibitors of 17b-HSD1 (Sweet et al 1991). Later, equilin (Fig.…”

Section: Inhibitors Of 17b-hsd1mentioning

confidence: 93%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

115

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Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17b-HSDs have been identified to date, and with one exception, 17b-HSD type 5 (17b-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17b-HSDs, reflecting the major redox activity at the 17b-position of the steroid, the activities of these 15 enzymes vary, with several of the 17b-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17b-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17b-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

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“…C16,C17-substituted pyrazole and isoxazole E 1 derivatives (Fig. 3d) have also been shown to be competitive inhibitors of 17b-HSD1 (Sweet et al 1991). Later, equilin (Fig.…”

Section: Inhibitors Of 17b-hsd1mentioning

confidence: 93%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

115

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“…All the aforementioned inhibitors contain a reactive functional group, which inactivates the enzyme by forming a stable covalent bond with the enzyme (irreversible inhibitors). However, the following categories of compounds were described as reversible inhibitors of 17β–HSD1: 1) estrone (E 1 ) derivatives with pyrazole or isoxazole fused to the 16,17 position on the D‐ring (26), 2) E 2 derivatives bearing a long 7α‐undecanamide side chain (27, 28), and 3) an E 2 derivative bearing a 6β‐thiaheptanamide side chain (29). 16‐Oxoestrone represents a special inhibitor because it was reversible at neutral pH 7.2 and irreversible at basic pH 8.5 (30).…”

mentioning

confidence: 99%

A concerted, rational design of type 1 17β‐hydroxysteroid dehydrogenase inhibitors: estradiol‐adenosine hybrids with high affinity

et al. 2002

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Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 1) catalyzes the final step in the synthesis of active estrogens that stimulate the proliferation of breast cancer cells. Based on the initial premise to make use of the binding energies of both the substrate and cofactor sites, and molecular modeling starting from the enzyme structure, several estradiol-adenosine hybrids were designed and synthesized. Among these hybrids, EM-1745 with a linker of 8-CH2 groups is proved to be the best competitive inhibitor with a Ki of 3.0 +/- 0.8 nM. The crystal structure of the EM-1745 enzyme complex at 1.6 A provides evidence at atomic resolution of strong interactions between both the steroid and cofactor moieties and the enzyme molecule, as illustrated by a deltaA-weighted 2Fo-Fc electron density map contoured at 3.0 delta. The substrate entry loop is further stabilized in this complex compared with previous complexes of the enzyme. These results confirm our initial strategy of combining studies of structural biology and enzyme mechanism in the inhibitor design, which may be applied to other steroidogenic enzymes involved in human diseases.

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“…[ 7–13 ] In detailed researches, steroidal heterocycles demonstrated potent cytotoxicity against the diverse cancer cells. [ 4,14–18 ] On the other side, natural steroids as a vital class of compounds displayed significant biological properties, [ 19 ] as well as natural steroidal alkaloids, are identified [ 20 ] to possess notable physiological activities. Hence, the researcher's efforts have been focused on the modification of novel heterocyclic steroids due to the great biological and pharmaceutical impacts as these steroids displayed antitumor, anti‐inflammatory, anabolic, androgenic, [ 21 ] antiproliferative, [ 5 ] antibacterial, anti‐proliferative, cytotoxic, [ 22 ] and anticancer activities.…”

Section: Introductionmentioning

confidence: 99%

Heterocyclic steroids: Synthetic routes and biological characteristics of steroidal fused bicyclic pyrimidines

Elattar

El‐Mekabaty

2020

Journal of Heterocyclic Chem

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Natural steroids are characterized as a vital class of compounds, a type of secondary metabolites and components of cell membranes that widely accessible in plants or animals displayed significant pharmacological and varied biological properties. The present study aims to highlight the conveyed researches of synthetic routes adopted to obtain the various structures of steroidal fused bicyclic pyrimidines with substantial biological and pharmaceutical importance. The topic was discussed in light of the synthesis of fused [6 + 5] bicyclic systems, fused [6 + 6] bicyclic systems, binary heterocycles, and biological applications. In detail, the various synthetic strategies for the construction of steroids fused to bicyclic pyrazolopyrimidines, thiazolopyrimidines, triazolopyrimidines, pyridopyrimidines, pyranopyrimidines, and binary pyrimidines were discussed. Heterocyclic steroids of this class of compounds demonstrated potent anticancer, anti‐proliferative, anti‐neuro‐inflammatory, anti‐inflammatory, and anti‐ulcer activities. It was perceived that the synthetic steroids of such bicyclic pyrimidine scaffolds are fused into the steroid basic skeleton is essential for the potent bioactivities.

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Hydrogen bonding in steroidogenesis: Studies on new heterocyclic analogs of estrone that inhibit human estradiol 17β-dehydrogenase

Cited by 28 publications

References 19 publications

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

A concerted, rational design of type 1 17β‐hydroxysteroid dehydrogenase inhibitors: estradiol‐adenosine hybrids with high affinity

Heterocyclic steroids: Synthetic routes and biological characteristics of steroidal fused bicyclic pyrimidines

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