Prenylation may turn a flavonoid from
Prenylation may turn a flavonoid from an agonist to an antagonist and improve the selectivity to both ERs depending on the position of the substitution. C-8 prenylation appears to promote antagonism to a larger extent than C-6 in ERα due to steric hindrance against generation of agonistic conformation. Prenylation affords naringenin a good ER modulatory activity that is supposed to be negligible. 8-Prenylnaringenin has a stronger agonistic activity to ERβ (EC50=50nM) than to ERα (EC50=124nM) . 8-Prenylgenistein has enhanced binding affinity to ERβ and improves trabecular bone properties by inhibiting the expression of RANKL/osteoprotegerin, alkaline phosphatase, type-1 collagen, osteocalcin, cathepsin K, and ERα in bone tissue of ovariectomized mice. However, unprenylated genistein gives a different phenotype by increasing the ERα expression . Xanthohumol is a prenylated chalcone present as a bioactive Adaptaquin of hops used in beer production. Xanthohumol prevents the interaction between brefeldin-A-inhibited guanine nucleotide exchange protein 3 (BIG3) and prohibitin 2 (PHB2), which releases the latter allowing it to bind to ERα, resulting in complete suppression of ERα signaling pathway and inhibition of breast cancer progress . Triggering the phosphorylation of ERK1/2 and p38 MAPK is another anticancer mechanism of xanthohumol. Several novel prenylated isoflavonoids (Ebenosin I–III) have been found in Onobrychis ebenoides and they show estrogenic activities in a cell-dependent manner . Psoralidin is a monoprenylated coumestrol and has better ER modulatory activity than coumestrol. It can work as an agonist to both ERα and ERβ. At 10 μM, psoralidin activates the reporter gene expression to the maximum . It shows an osteoprotective effect through ER signaling pathway . The osteoblast proliferation and differentiation are promoted, along with increased formation of alkaline phosphatase colony and calcified nodules, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin, and osteopontin. The expression of insulin-like growth factor 1, β-catenin, runt-related transcription factor 2 (RUNX2), osterix, and osteoprotegerin is induced, leading to inhibition of osteoclast formation and osteoclastic bone resorption . It is worth mentioning that furan and pyran prenylation may lead to antagonistic activity for phytoestrogens. Pyran prenylation transforms daidzein from an ER agonist to an antagonist . Glyceollin II acts as an ER antagonist, which is the prenyl cyclization product of glyceollidin II, an ER agonist .
Heterologous Synthesis of Phytoestrogens
Concluding Remarks ERs are positively involved in physiological behavior of humans. Regulation of ER signaling pathways can help to maintain health status and treat diseases. Phytoestrogens are good candidates as ER modulators due to high safety and good performance, even though weaker than synthesized commercial ER modulators. By using modern techniques, like computer simulation, to search for selective ERα/ERβ agonists/antagonists from a natural product database, more potent phytoestrogens with specific functions will be found. Through de novo heterologous synthesis of these chemicals, it is possible to produce any desired phytoestrogens in an efficient way. This technique solves the quantity limits of phytoestrogens in nature and makes them available for industrial applications. The quick development of natural product research and metabolic engineering technique will bring more benefits to human health. There are some questions that need to be solved in the future (see Outstanding Questions). Answering these questions will be good to utilize and prepare phytoestrogens.
Acknowledgments The authors appreciate the financial support from National Natural Science Foundation of China (31871851 and 31671906), National Key Research and Development Program of China (2017YFD0401301), Frontier Science Key Program of Chinese Academy of Sciences (QYZDB-SSW-SMC018) and Youth Innovation Promotion Association of Chinese Academy of Sciences (2011252).