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In addition to its activity as an aromatase inhibitor, ..

This review summarizes the most recent advances in the search for natural product aromatase inhibitors. We focus primarily on natural compounds that have been reported in the two year period (February 2008 – January 2010) since the publication of our previous comprehensive review of natural product AIs that covered all of the relevant literature up to January 2008 []. Discussion of active compounds is organized based on aromatase activity in enzyme versus cellular and in vivo bioassays since the level of information provided by these types of assays can be drastically different. These more recent accounts will then be compared with the most potently active natural product AIs summarized in our previous review [], followed by a discussion of the current research trends in AI research and future directions for natural product AIs.

Discussion of active compounds is organized based on aromatase activity in enzyme versus ..

Natural product aromatase research has continued to produce exciting, potent aromatase inhibitory lead compounds that provide interesting new avenues of investigation. Several natural compounds have recently been identified to exhibit nanomolar levels of inhibition of the aromatase enzyme, both in noncellular and cellular AI assays, as well as exhibiting activity using in vivo mouse and zebrafish models. Many of these potent natural product AIs need further investigation to help determine their potential for preclinical and clinical development. Several of the compounds in this review could be the subject of extensive medicinal chemistry to modify the natural product scaffold, in the search for more potent AIs.

Aromatase inhibitors block the synthesis of ..

responsible for their conversion into flavanones and .

So if there are already clinically available AIs, why search for additional compounds that inhibit aromatase, inclusive of natural products? AIs do have several side effects, such as those listed above, but also lead to more severe side effects including effects on the bones, brain, and heart [], []. Natural products with a long history of use, such as those from foods or from traditional medicines, that also exhibit aromatase inhibitory activity, may have less associated toxicity. Furthermore, natural compounds might help in the search for promoter-specific AIs, a new direction in AI research, and thus selectively target aromatase in the breast and reduce systemic toxicity.

Several synthetic aromatase inhibitors are currently in clinical use for the treatment of postmenopausal women with hormone-receptor positive breast cancer. However, these treatments may lead to untoward side effects and so the search for new aromatase inhibitors continues, especially those for which the activity is promoter-specific, targeting the breast-specific promoters I.3 and II. Recently, numerous natural compounds have been found to inhibit aromatase in noncellular, cellular, and in vivo studies. These investigations, covering the last two years, as well as additional studies that have focused on the evaluation of natural compounds as promoter-specific aromatase inhibitors or as aromatase inducers, are described in this review.

AROMATASE INHIBITORS: A NEW HOPE FOR BREAST …

Aromatase activity is present in the fat tissues, ..

Several of the compounds that have been reported to inhibit aromatase during the past two years have also previously undergone testing for AI activity as reported in our previous review []. Apigenin (16) was found to be strongly active in microsomes in recent studies, which was also the case for much of the previous AI research on this compound, including noncellular and cellular tests. Myricetin (14) was also recently reported as a moderately active inhibitor of aromatase, consistent with previous literature reports on this compound. Biochanin A (19) was also recently found to be strongly active in cellular AI screening, whereas in previous studies the results for this compound were mixed, with some indicating inhibition of aromatase and others reporting inactivity. Isoliquiritigenin (9) and EGCG (26) were active in recent AI testing, and, as with biochanin A, these two compounds had previously been shown to have ambiguous aromatase activity. Two of the compounds reported herein as active, berberine (25) and genistein (27), have previously undergone AI testing and were found to be inactive in other assay systems. In the case of contradictory or ambiguous AI results for the same compounds, several possible variables should be considered, including the use of different assay systems (as mentioned above) and variations in the levels of compound purity, among others.

Commercially purchased isoliquiritigenin (9) was found to be an active AI in three different test systems. In MCF-4aro cells (MCF-7 cells transfected with human CYP19), isoliquiritigenin was found to inhibit aromatase in a potent manner with a Ki of 3 µM []. They next tested isoliquiritigenin in a xenograft mouse model using athymic mice transplanted with MCF-7aro cells and found that the compound significantly suppressed xenograft growth (administered through feeding with doses of 0, 50, 150, or 500 ppm isoliquiritigenin supplementation). Finally, the effect of isoliquiritigenin was explored on specific aromatase promoters, namely, promoters I.3 and II, which are known to be breast-tissue specific, with the results indicating that the compound acts in a promoter-specific manner.

Melatonin modulates aromatase activity in MCF-7 human ..
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on the local synthesis of estrogens had ..

Apart from these inhibitors there is a class of naturally occurring compounds, flavanoids which also shown activity towards aromatase inhibition, thus lowering the estrogen biosynthesis and circulating estrogen levels 26. It has been seen that these natural products present in soy and in rye flour, are dietary factor that may be responsible for the lower incidence of breast cancer in certain regions of the world 27. Generally, flavones and flavanones have higher aromatase inhibitory than isoflavones. Chrysin, 7- hydroxyflavone, the most potent flavones, inhibitor of aromatase 28. But poor oral bioavailability is major limitation for the success of use of dietary flavanoids as chemopreventive agents.

Natural aromatase inhibitors | Estrogen | Biochemistry

Aromatase Inhibitors: Aromatase Inhibitors are of two types differing in their chemical structure and mechanism of action: steroidal type and non-steroidal type inhibitors as shown in Fig 2. The steroidal inhibitors are analogues of androstenedione, a natural substrate of aromatase and act initially as competitive-substrate mimics. These agents become strongly bound to the binding site of the enzyme and then converted to reactive intermediates that bind covalently to the enzyme. As such, they are known as aromatase inactivators 21.eg, exemestane, formestane.

Read papers from the keyword Chrysin AND Aromatase with ..

Designing of Aromatase Inhibitors: Inhibitors for aromatase are designed by studying the active sites of the enzyme and through molecular modeling studies. Early studies focused on energy minimization calculations, conformational analysis, molecular volume calculations, pharmacophore mapping of aromatase inhibitors 44, 45. Recently the comparative Molecular Field Analysis (COMFA) 3D-QSAR method was applied to the analysis of non-steroidal aromatase inhibitors, correlating the inhibitory activity with steric field value 46. The major interaction for non-steroidal aromatase inhibitors is through the coordination bond of suitably placed heteroatoms with iron of the heme. The 3D-QSAR studies show the presence of two hydrophobic binding pockets in the C6 region of the steroid. One of this is large and in the α-face while another is smaller and located in the β-face 47. This hydrophobic pocket is constituted by highly hydrophobic aliphatic amino group I 305, A 306, T 310, V 369, V 370, L 477. The putative ligands are expected to have non-polar interaction with amino acids in the active site. The selective inhibition of aromatase can be attributed to the formation of hydrogen bond by acceptor group present in ligand along with the hydroxyl group of S 478 22. Thus a ligand should possess the following characteristic for selective inhibition of aromatase enzyme:

flavanones, catechins) exert ..

Aromatase Inhitors for Postmenopausal Women: Before menopause, the ovaries produce most of a woman's estrogen, so reducing estrogen from other sources has little or no effect. But in post-menopausal women, most of the body's estrogen is made from another hormone, androgen. Aromatase inhibitors stop the enzyme called aromatase from turning androgen into estrogen, lowering the amount of estrogen produced outside the ovaries19. That means less estrogen in the bloodstream, less estrogen reaching estrogen receptors, and less cancer cell growth. Also, two-third of breast tumors demonstrates aromatase activity, making this enzyme a likely source of local estrogen for breast cancer cells.

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