Foreword

Polyphenols are widely present in foods such as fruits and beverages, and in medicinal plants. Polyphenols also feature various functionalities, including antitumor, antimutagenicity, and antiviral activity. Dietary polyphenols are known to possess antioxidant effects, and it is expected that daily intake of these polyphenols will contribute to the prevention of various diseases caused by oxidative stress. Against this background, research into the absorption, metabolism, and excretion of flavonoids, anthocyanins and ellagitannins among dietary polyphenols is actively in progress, and the existence of bioactive metabolites has become clear. A bioactive ellagitannin metabolite, urolithin A, reported to show mitophagy induction, prolonged lifespan in Caenorhabditis elegans, and enhanced muscle function in rodents,¹⁾ is under study as a drug candidate compound. Nevertheless, there remain many unclear points about the chemical, physical and biological properties of various polyphenols. In this Current Topics section of the Chemical and Pharmaceutical Bulletin, I introduce new research developments regarding polyphenols, in three review articles and one regular article, by four groups actively involved in polyphenol research.

The review article entitled “Stiffening of Cancer Cell Membranes Is a Key Biophysical Mechanism of Primary and Tertiary Cancer Prevention with Green Tea Polyphenols,” by Dr. Masami Suganuma et al., summarizes the possibility of an effective use of a green tea polyphenol, (−)-epigallocatechin gallate (EGCG), in primary and tertiary cancer prevention and treatment. It is no exaggeration to say that research on polyphenols in Japan has progressed significantly with green tea polyphenols. EGCG has been intensively studied as a primary cancer preventive agent for healthy populations, and clinical trials of EGCG for tertiary cancer prevention among people who have experienced cancer are in progress. This suggests that green tea polyphenols have potential clinical implications for cancer treatment. The authors investigated the inhibition of motility, probable metastasis, stemness properties and immune escape mechanisms by treatment with EGCG. The effects of several polyphenols, including curcumin, diallyl sulfide, shogaol and resveratrol, on the stiffness of cells, phosphorylated AXL, and tumor sphere formation were evaluated. Curcumin showed similar effects to EGCG, and enhanced the stiffness of lung cancer cells, along with reducing phosphorylated AXL stimulated by Gas6, as well as the number of tumor spheres. The authors write that these results indicate that stiffening of a cancer cell membrane is a commonly underlying mechanism that may explain diversified beneficial effects of green tea polyphenols. This review proposed that examination of membrane stiffening should be an effective strategy for developing new drugs for tertiary cancer prevention and treatment.

“Production Mechanisms of Black Tea Polyphenols,” by Drs. Takashi Tanaka and Yosuke Matsuo, focuses on the production and characteristics of complex black tea polyphenols. Black tea is the most popular tea in the world; its polyphenols are produced by enzymatic oxidation during tea fermentation. Although the isolation and characterization of only dimeric oxidation products, such as theaflavin, theasinensin, and theacitrin, from black tea have been reported, details of this chemical mechanism remain unclear due to the complexity and heterogeneity of the oxidation products. The authors have described current knowledge of typical black tea polyphenol production mechanisms, and present recent advances in the characterization of thearubigins. They have also investigated the separation and isolation of polyphenols from black tea, and analyzed black tea polyphenols using HPLC-MS. Fourteen catechin-oxidized products were isolated, and their structures were characterized. Furthermore, the mechanism of formation of tea polyphenol production was clarified based on chemical methods. However, the major polyphenol in black tea has not been properly characterized to date, and the complete definition of this polyphenol remains unexplained. In this review, chemical approaches to understanding the mechanisms of tea polyphenol production were evaluated, in hopes of clarifying tea polyphenol chemistry.

“Development of High-Order Functions Using (－)-Epigallocatechin-3-O-gallate in Water,” by Dr. Takashi Ishizu, describes chemical approaches to molecular capture and chiral recognition of EGCG. The author investigated the high-order functions of molecular capture and chiral recognition of tea polyphenol, EGCG, in water. The molecular capture capacity of various heterocyclic compounds using EGCG appears to depend on the structure of the heterocyclic compounds themselves, as well as physical factors such as the degree of polymerization, entropy, and solubility of the EGCG complex. Furthermore, the interaction of EGCG with diketopiperazine cyclo(L-Pro-Gly), cyclo(D-Pro-Gly) was evaluated based on X-ray crystallography and ¹H-NMR. The results suggested that the chiral space of EGCG recognizes the chirality of the compounds contained in that space. In addition, chiral recognition by EGCG of the drugs propranolol, proxyphyllin, and dipropyllin was tested. In the ¹H-NMR spectrum in D₂O solution of lasemiproxylline and diprophylline in the presence of EGCG, specific signals of lasemiproxylline and diprophylline were clearly observed as two singlets, indicating higher-order functions for molecular capture. These results suggest the potential for developing high-order functions of molecular capture and chiral recognition using EGCG. The author proposed that the desired enantiomer could be easily isolated from an aqueous solution as a precipitate, or, conversely, the undesired enantiomer could be removed from the solution as a precipitate using EGCG or its derivatives.

“Novel Hybrid Molecules Based on (－)-Epigallocatechin Gallate as Potent Anti-adipogenic Agents,” a regular article presented by Dr. Tae Hoon Kim and his colleagues, deals with molecular hybridization of EGCG using dielectric barrier discharge (DBD) plasma irradiation and monitoring the biological activity of the hybrid compounds. Molecular hybridization is a valuable direct new approach to the design of new prototypes and structural changes based on recognition of the units that make up the pharmacophore. DBD plasma treatment has proven to be an effective advanced technique applied to food processing, and is known to play a major role in microbial destruction due to its abundance of reactive species. The authors investigated the DBD plasma exposure of major natural products, and evaluated biological properties of chemical hybridization. In this article, EGCG and phloroglucinol were exposed to DBD plasma; the subsequent ability to induce chemical hybridization and anti-lipolysis of the resulting compounds was evaluated. Four new structures of hybrid molecules induced by cold plasma irradiation were isolated and identified based on several spectroscopic analyses. Among the generated novel hybrids, triphloro EGCG exhibited significantly improved anti-adipogenic property, as measured toward both pancreatic lipase and preadipocyte differentiation in 3T3-L1 compared to the original EGCG and phloroglucinol. This article is the first to report analyses of the hybridization profile of exposed EGCG and phloroglucinol under DBD plasma, and the resulting novel hybrid compound represents an interesting subclass of anti-adipogenic candidates.

The organizer believes that these review and regular articles provide useful information for future research into various polyphenols, whether by chemical, physiological, and biological approaches, and sincerely appreciates all authors for their significant contributions.

References

• 1) Ryu D., Mouchiroud L., Andreux P. A., Katsyuba E., Moullan N., Nicolet-Dit-Félix A. A., Williams E. G., Jha P., Sasso G. L., Huzard D., Aebischer P., Sandi C., Rinsch C., Auwerx J., Nat. Med., 22, 879–888 (2016).