New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

<p>Abstract</p> <p>Background</p> <p>Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds <b>3a </b>and <b>4a</b>, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells.</p> <p>Results</p> <p>The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G₀/G₁phase and inducing cell death with features of apoptosis and autophagic cell death.</p> <p>Conclusion</p> <p>Our <it>in vitro </it>studies showed that the two steroidal AIs, <b>3a </b>and <b>4a</b>, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G₀/G₁phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.</p

Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity

An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ with m-CPBA has led to the neurosteroids 3[alpha]-hydroxy- and 3[alpha],21-dihydroxy-5[alpha]-pregnanolones. Using testosterone as starting material, a new short synthesis of an aromatase inhibitor, 4-OHA, has been achieved through hydroboration/oxidation followed by a Swern type oxidation and epimerization. Another aromatase inhibitor, androst-4-ene-3,6-17-trione, has been efficiently prepared using PCC on montmorillonite K10, under ultrasonic irradiation.http://www.sciencedirect.com/science/article/B6THR-3WC46V7-8/1/5f915790e78df65f4c988ab78bf4f17

Synthesis and biochemical studies of 17-substituted androst-3-enes and 3,4-epoxyandrostanes as aromatase inhibitors

http://www.sciencedirect.com/science/article/B6TC9-4T0WJXG-2/2/58305e64e3c068f352293a693f168db

The Structural Diversity and Biological Activity of Steroid Oximes

Steroids and their derivatives have been the subject of extensive research among investigators due to their wide range of pharmacological properties, in which steroidal oximes are included. Oximes are a chemical group with the general formula R1R2C=N&minus;OH and they exist as colorless crystals and are poorly soluble in water. Oximes can be easily obtained through the condensation of aldehydes or ketones with various amine derivatives, making them a very interesting chemical group in medicinal chemistry for the design of drugs as potential treatments for several diseases. In this review, we will focus on the different biological activities displayed by steroidal oximes such as anticancer, anti-inflammatory, antibacterial, antifungal and antiviral, among others, as well as their respective mechanisms of action. An overview of the chemistry of oximes will also be reported, and several steroidal oximes that are in clinical trials or already used as drugs are described. An extensive literature search was performed on three main databases&mdash;PubMed, Web of Science, and Google Scholar

The Structural Diversity and Biological Activity of Steroid Oximes

Steroids and their derivatives have been the subject of extensive research among investigators due to their wide range of pharmacological properties, in which steroidal oximes are included. Oximes are a chemical group with the general formula R1R2C=N−OH and they exist as colorless crystals and are poorly soluble in water. Oximes can be easily obtained through the condensation of aldehydes or ketones with various amine derivatives, making them a very interesting chemical group in medicinal chemistry for the design of drugs as potential treatments for several diseases. In this review, we will focus on the different biological activities displayed by steroidal oximes such as anticancer, anti-inflammatory, antibacterial, antifungal and antiviral, among others, as well as their respective mechanisms of action. An overview of the chemistry of oximes will also be reported, and several steroidal oximes that are in clinical trials or already used as drugs are described. An extensive literature search was performed on three main databases—PubMed, Web of Science, and Google Scholar

Plant derived and dietary phenolic antioxidants: Anticancer properties

n this paper, a review of the literature on the phenolic compounds with anticancer activity published between 2008 and 2012 is presented. In this overview only phenolic antioxidant compounds that display significant anticancer activity have been described. In the first part of this review, the oxidative and nitrosative stress relation with cancer are described. In the second part, the plant-derived food extracts, containing identified phenolic antioxidants, the phenolic antioxidants isolated from plants and plant-derived food or commercially available and the synthetic ones, along with the type of cancer and cells where they exert anticancer activity, are described and summarized in tables. The principal mechanisms for their anti-proliferative effects were also described. Finally, a critical analysis of the studies and directions for future research are included in the conclusion

New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death-3

H the indicated concentrations of the compounds in medium containing 1 nM T. Cells cultured with testosterone represented maximum cell proliferation and were considered as control. 3a and 4a induced a decrease in cell proliferation, evaluated by the thymidine incorporation assay, in a time- and dose-dependent manner. Results are the mean ± SE of three independent experiments whereas cultures were performed in triplicate. Significant inhibition relative to the control level is denoted by * (< 0.001), ** (P < 0.01) and θ (P < 0.05).<p><b>Copyright information:</b></p><p>Taken from "New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death"</p><p>http://www.biomedcentral.com/1471-2121/9/41</p><p>BMC Cell Biology 2008;9():41-41.</p><p>Published online 24 Jul 2008</p><p>PMCID:PMC2515307.</p><p></p

New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death-5

an increase in annexin V binding in MCF-7aro cells, in comparison to 9.2% of the control (medium containing 1 nM T, open histograms). Numbers in histograms are percent of annexin V-positive cells after treatment with the compounds. The histograms correspond to cells gated for negative 7-AAD staining. Data are representative of triplicate cultures and the figure is representative of three independent experiments.<p><b>Copyright information:</b></p><p>Taken from "New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death"</p><p>http://www.biomedcentral.com/1471-2121/9/41</p><p>BMC Cell Biology 2008;9():41-41.</p><p>Published online 24 Jul 2008</p><p>PMCID:PMC2515307.</p><p></p

New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death-1

for 72 hr. Wright staining shows that cells treated with 4a have condensed and marginalized chromatin (arrowheads) and cytoplasm vacuolization (arrows) (C) in comparison to the control cells (A). Nuclear morphological changes in MCF-7aro cells were demonstrated by Hoechst 33258 staining under the fluorescence microscope. Untreated cells exhibited normal nuclear morphology and the presence of abundant mitotic figures (open arrows) (B). Treatment with 4a induced chromatin condensation (arrows) (D).<p><b>Copyright information:</b></p><p>Taken from "New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death"</p><p>http://www.biomedcentral.com/1471-2121/9/41</p><p>BMC Cell Biology 2008;9():41-41.</p><p>Published online 24 Jul 2008</p><p>PMCID:PMC2515307.</p><p></p

New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death-6

72 hr incubation with the compounds, cells were treated with MDC for 1 hr at 37°C, washed with PBS and analysed by fluorescence microscopy. The formation of autophagic vacuoles in MCF-7aro cells treated with compound 4a was indicated by punctuated MDC labelling in the cytoplasm.<p><b>Copyright information:</b></p><p>Taken from "New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death"</p><p>http://www.biomedcentral.com/1471-2121/9/41</p><p>BMC Cell Biology 2008;9():41-41.</p><p>Published online 24 Jul 2008</p><p>PMCID:PMC2515307.</p><p></p