Structure-Activity Relationship of Oligomeric Flavan-3-ols: Importance of the Upper-Unit B-ring Hydroxyl Groups in the Dimeric Structure for Strong Activities.

Yoshitomo Hamada,Noriyuki Nakajima,Syuhei Okamoto,Akiko Saito,Takahiro Koashi,Yoshihiro Ayano,Masahiro Tokunaga,Masahiro Hamada,Masahiko Ishida,Syoma Doi,Takashi Kawasaki,Syota Takano

doi:10.3390/molecules201018870

Abstract

Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks) and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4–8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae) and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (−)-epigallocatechin-[4,8]-(+)-catechin, (−)-epigallocatechin-[4,8]-(−)-epigallocatechin, (−)-epigallocatechin-[4,8]-(−)-epigallocatechin-3-O-gallate, and (+)-catechin-[4,8]-(−)-epigallocatechin and performed structure–activity relationship (SAR) studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l-picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity.

Highlights

There is great interest in the strong biological activity of compounds commonly found in some foods
(10) to determine which part is the most important for biological activities and if the total number of phenolic hydroxyl groups in the entire molecule correlates with biological properties
The synthesized compounds 7–10 are natural products that can be isolated from beverages, e.g., green tea [24] and beer [25], and are known as strongly bioactive polyphenols

Summary

Introduction

There is great interest in the strong biological activity of compounds commonly found in some foods. We demonstrated that galloyl modification of the hydroxyl groups of flavan-3-ols enhanced their biological activities [15,16,17,18]. We further reported the synthesis of semi-acetylated analogues 1–3 of procyanidin B1, a dimeric flavan-3-ol, and discussed their inhibitory activities against HeLa S3 cell proliferation (Figure 1). HeLa S3 cells, whereas procyanidin B1 (1) and the upper-unit acetylated analog 3 showed no inhibitory activity [19]. These results indicated that the upper-unit of dimeric flavan-3-ol is critical for biological activity. We proved that the stereochemistry of the 3-hydroxyl group of flavan-3-ol-3,5-di-O-gallate is important for inhibitory activity against HeLa S3 cell proliferation [20]. We confirmed the importance of the upper-unit for the functionality of dimeric flavan-3-ols

Results and Discussion

DPPH Radical Scavenging Activity

General Information

Inhibitory Activity of HeLa S3 Cell Proliferation

Conclusions