Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Abstract

The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importance in medicine. Some of these natural compounds have been shown to modulate key human metabolic processes via steroidal hormone receptors, or to inhibit crucial enzymes involved in the biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as genistein are well known for this "phytoestrogenic" biological activity. This review focuses on the ability of select polyphenolics and their synthetic derivatives to function as steroidal mimics in the inhibition of the enzyme aromatase, thereby lowering production of endogenous estrogen growth hormones. The discovery of potent, natural product-based aromatase inhibitors (AIs) as hit compounds has led to the introduction of steroidal-based irreversible inhibitors, such as exemestane and reversible AIs such as anastrozole and letrozole, now standard therapy in the treatment of estrogen receptor-positive breast cancer and other hormone related indications. Pursuit of this strategy over the last few decades has been largely successful although complications and challenges remain. This review highlights the aromatase activity of natural stilbenes, chalcones, and flavanones and synthetically inspired versions thereof and draws attention to new and under-investigated areas within each class worthy of pursuit.

Prospective association of dietary soy and fibre intake with puberty timing: a cohort study among Chinese children

“…Although the mechanism underlying the association between soy intake (isoflavone) and puberty timing remains unknown, we speculate that possible explanations are: isoflavone is structurally and functionally similar to endogenous oestrogen [ 6 ] and could inhibit the activity of aromatase, the rate-limiting enzyme of oestrogen biosynthesis [ 44 ], therefore possibly affecting endocrine homeostasis and further pubertal development. Conversely, isoflavones have been reported to directly bind to and influence the expression of oestrogen receptors (ERs) [ 45 ] and impact the hypothalamus-pituitary-gonadal (HPG) axis [ 46 ].…”

Consumption of flavonoids and risk of hormone-related cancers: a systematic review and meta-analysis of observational studies

“…Besides, flavonoids seem to have hormone-like and anti-hormone effects due to their structural similarity to the natural estrogen estradiol, as well as other steroid hormones and steroid hormone antagonists [ 15 ]. Further, there is evidence that certain flavonoids may inhibit the activity of aromatase, an enzyme that catalyzes the conversion of androgen to estrogen, and up-regulation of the latter can promote the development of HRCs [ 16 ].…”

<p>Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms</p>

“…These compounds are able to modulate several estrogen activating enzymes (CYP19, CYP1B1) and to induce the expression of cytoprotective enzymes (SOD3, NQO1, GST, COMT, CYP1A1, etc.) as indicated in Table 1 through Nrf2-dependent and independent mechanisms 17,18,21,22,24,25,43,61–66. Importantly, Nrf2 is a basic leucine zipper stress-sensitive transcription factor that maintains redox homeostasis by inducing the transcription of several cytoprotective genes through ARE/electrophile response elements in target gene promoters 59,60.…”