Synthesis of 16β-derivatives of 3-(2-bromoethyl)-estra-1,3,5(10)-trien-17β-ol as inhibitors of 17β-HSD1 and/or steroid sulfatase for the treatment of estrogen-dependent diseases

Lespérance, Maxime; Roy, Jenny; Ngueta, Adrien Djiemeny; Maltais, René; Poirier, Donald

doi:10.1016/j.steroids.2021.108856

Cited by 7 publications

(7 citation statements)

References 44 publications

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“…In case of steroidal HSD17B1 inhibitors, carbons 6, 15, 16, and 17 of the steroid backbone have been modified. The team of Dr. Poirier developed a series of estradiol derivatives with C16 beta-mcarbamoylbenzyl modifications (Lesperance et al, 2021). CC-156, the first developed, showed some estrogenic action, which was eliminated upon C3-bromoethyl modification, leading to compound PBRM and subsequent analogues.…”

Section: Overview Of Hsd17b1 Inhibitorsmentioning

confidence: 99%

“…CC-156, the first developed, showed some estrogenic action, which was eliminated upon C3-bromoethyl modification, leading to compound PBRM and subsequent analogues. The inhibitory potency of the lead molecule has been improved displaying EC50 as low as 68 nM in-vitro on monolayer cells (Lesperance et al, 2021). Further, the authors were able to add STS inhibitory properties to the molecule by including one or two sulfamate groups in the steroid D-ring (Lesperance et al, 2021).…”

Section: Overview Of Hsd17b1 Inhibitorsmentioning

confidence: 99%

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Targeting the formation of estrogens for treatment of hormone dependent diseases–current status

Rižner¹,

Romano²

2023

Front. Pharmacol.

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Local formation and action of estrogens have crucial roles in hormone dependent cancers and benign diseases like endometriosis. Drugs that are currently used for the treatment of these diseases act at the receptor and at the pre-receptor levels, targeting the local formation of estrogens. Since 1980s the local formation of estrogens has been targeted by inhibitors of aromatase that catalyses their formation from androgens. Steroidal and non-steroidal inhibitors have successfully been used to treat postmenopausal breast cancer and have also been evaluated in clinical studies in patients with endometrial, ovarian cancers and endometriosis. Over the past decade also inhibitors of sulfatase that catalyses the hydrolysis of inactive estrogen-sulfates entered clinical trials for treatment of breast, endometrial cancers and endometriosis, with clinical effects observed primarily in breast cancer. More recently, inhibitors of 17beta-hydroxysteroid dehydrogenase 1, an enzyme responsible for formation of the most potent estrogen, estradiol, have shown promising results in preclinical studies and have already entered clinical evaluation for endometriosis. This review aims to provide an overview of the current status of the use of hormonal drugs for the major hormone-dependent diseases. Further, it aims to explain the mechanisms behind the -sometimes- observed weak effects and low therapeutic efficacy of these drugs and the possibilities and the advantages of combined treatments targeting several enzymes in the local estrogen formation, or drugs acting with different therapeutic mechanisms.

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Section: Overview Of Hsd17b1 Inhibitorsmentioning

confidence: 99%

Section: Overview Of Hsd17b1 Inhibitorsmentioning

confidence: 99%

Targeting the formation of estrogens for treatment of hormone dependent diseases–current status

Rižner¹,

Romano²

2023

Front. Pharmacol.

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“…Since experimental evidence showed that the simultaneous inhibition of STS and 17β-HSD1 enzymes was more effective than blockage of each protein alone [ 19 ], a new family of steroid derivatives with dual inhibiting actions was designed and synthesized. Some of them are under biological evaluation [ 20 , 21 ].…”

Section: Alternative Therapeutic Approach: Inhibition Of the Enzymes ...mentioning

confidence: 99%

De novo cholesterol biosynthesis: an additional therapeutic target for the treatment of postmenopausal breast cancer with excessive adipose tissue

Coradini

2022

Exploration of Targeted Anti-Tumor Therapy

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The onset and development of breast cancer in postmenopausal women are associated with closely related individual-dependent factors, including weight gain and high levels of circulating androgens. Adipose tissue is the most peripheral site of aromatase enzyme synthesis; therefore, the excessive accumulation of visceral fat results in increased androgens aromatization and estradiol production that provides the microenvironment favorable to tumorigenesis in mammary epithelial cells expressing estrogen receptors (ERs). Moreover, to meet the increased requirement of cholesterol for cell membrane assembly and the production of steroid hormones to sustain their proliferation, ER-positive cells activate de novo cholesterol biosynthesis and subsequent steroidogenesis. Several approaches have been followed to neutralize the de novo cholesterol synthesis, including specific enzyme inhibitors, statins, and, more recently, metformin. Cumulating evidence indicated that inhibiting cholesterol biosynthesis by statins and metformin may be a promising therapeutic strategy to block breast cancer progression. Unlike antiestrogens and aromatase inhibitors (AIs) which compete for binding to ER and inhibit androgens aromatization, respectively, statins block the production of mevalonic acid by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and metformin hampers the activation of the sterol regulatory element-binding protein 2 (SREBP2) transcription factor, thus inhibiting the synthesis of several enzymes involved in cholesterol biosynthesis. Noteworthy, statins and metformin not only improve the prognosis of overweight patients with ER-positive cancer but also improve the prognosis of patients with triple-negative breast cancer, the aggressive tumor subtype that lacks, at present, specific therapy.

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“…In continuation of our work on 17β-HSD1 inhibitors [ 21 , 22 , 23 , 24 , 25 ], we have synthesized and characterized the E1 derivative, compound 5 , as well as two E2 derivatives, compounds 6 and 10 ( Figure 3 ). Compound 10 is a hybrid molecule of ether-derivative 6 and EM-251, the latter being a known inhibitor of 17β-HSD1 [ 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

et al. 2023

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Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrogen-dependent diseases. In order to obtain new inhibitors of 17β-HSD1, the impact of a m-carbamoylphenyloxy group at position three of an estrane nucleus was evaluated by preparing three derivatives of estrone (E1) and E2 using a microwave-assisted synthesis of diaryl ethers. Their inhibitory activity was addressed on two cell lines (T-47D and Z-12) representative of breast cancer and endometriosis, respectively, but unlike T-47D cells, Z-12 cells were not found suitable for testing potential 17β-HSD1 inhibitors. Thus, the addition of the m-carbamoylphenyl group at C3 of E1 (compound 5) did not increase the inhibition of E1 to E2 transformation by 17β-HSD1 present in T-47D cells (IC50 = 0.31 and 0.21 μM for 5 and E1, respectively), and this negative effect was more obvious for E2 derivatives 6 and 10 (IC50 = 1.2 and 1.3 μM, respectively). Molecular docking allowed us to identify key interactions with 17β-HSD1 and to highlight these new inhibitors’ actions through an opposite orientation than natural enzyme substrate E1′s classical one. Furthermore, molecular modeling experiments explain the better inhibitory activity of E1-ether derivative 5, as opposed to the E2-ether derivatives 6 and 10. Finally, when tested on T-47D and Z-12 cells, compounds 5, 6 and 10 did not stimulate the proliferation of these two estrogen-dependent cell lines. In fact, they reduced it.

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Synthesis of 16β-derivatives of 3-(2-bromoethyl)-estra-1,3,5(10)-trien-17β-ol as inhibitors of 17β-HSD1 and/or steroid sulfatase for the treatment of estrogen-dependent diseases

Cited by 7 publications

References 44 publications

Targeting the formation of estrogens for treatment of hormone dependent diseases–current status

Targeting the formation of estrogens for treatment of hormone dependent diseases–current status

De novo cholesterol biosynthesis: an additional therapeutic target for the treatment of postmenopausal breast cancer with excessive adipose tissue

Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

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