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Proanthocyanidins, also known as condensed tannins or oligomeric flavonoids, are found in many edible plants and exhibit interesting biological activities. Herein, we report a new, simple method for the stereoselective synthesis of procyanidin B6, a (+)-catechin-(4-6)-(+)-catechin dimer, by Lewis acid-catalyzed intramolecular condensation. The 5-O-t-butyldimethylsilyl (TBDMS) group of 5,7,3′4′-tetra-O-TBDMS-(+)-catechin was regioselectively removed using trifluoroacetic acid, leading to the “regio-controlled” synthesis of procyanidin B6. The 5-hydroxyl group of the 7,3′,4′-tri-O-TBDMS-(+)-catechin nucleophile and the 3-hydroxyl group of 5,7,3′,4′-tetra-O-benzylated-(+)-catechin electrophile were connected with an azelaic acid. The subsequent SnCl4-catalyzed intramolecular condensation proceeded smoothly to give the 4-6-condensed catechin dimer. This is the first report on the complete regioselective synthesis of a 4-6-connected oligomer without modifying the 8-position.

Proanthocyanidins, also known as condensed tannins and/or oligomeric flavonoids, occur in many edible plants and have various interesting biological activities. Previously, we reported a synthetic method for the preparation of various procyanidins in pure form and described their biological activities. Here, we describe the synthesis of procyanidin B 1 acetylated analogs and discuss their inhibition activities against HeLa S3 cell proliferation. Surprisingly, the lower-unit acetylated procyanidin B 1 strongly inhibited the proliferation of HeLa S3 cells. This molecule showed much stronger inhibitory activity than did epigallocatechin-3-O-gallate (EGCG), green tea polyphenol, and dimeric compounds that included EGCG as a unit. This result suggests that the phenolic hydroxyl groups of the upper-units in flavan-3-ols are important for their inhibitory activity against cancer cell proliferation and that a hydrophobic lower unit dimer enhances this activity.

No abstract

Flavan-3-ol derivatives are common plant-derived bioactive compounds with strong various biological activities. In particular, (-)-epigallocatechin-3-O-gallate exhibits a variety of moderate biological activities without severe toxicity. Its health-promoting effects have been widely studied because it is a main ingredient in green tea and is commercially available at low cost. In general, the galloyl moieties of flavan-3-ol derivatives are thought to be essential to their strong biological activities. However, it is not clear which position is most effective for modification with the galloyl moiety to strengthen the biological activities because various galloylated analogs are difficult to obtain in pure form in a quantity large enough for assays. Therefore, we synthesized various galloylated flavan-3-ol derivatives in a stereoselective and regioselective manner. We reported in a previous paper that 3,5-digalloyl-(-)-epicatechin displayed much stronger inhibitory activity than 3,5-digalloyl-(+)-catechin did against HeLa S3 cell proliferation. In this study, we describe synthetic studies of 7-galloyl-and 3,7-digalloyl-modified (-)-epicatechin and (+)-catechin and compared their biological activities, HeLa S3 cell proliferation inhibitory activity and DPPH radical scavenging activity with those of 3,5-digalloyl-(-)-epicatechin. The results indicated that 3,7-digalloyl derivative did not inhibit HeLa S3 cell proliferation. Furthermore, 3,5-digalloyl-(-)-epigallocatechin was synthesized to evaluate the importance of the number of phenolic hydroxyl groups on the B-ring. Contrary to our expectations, 3,5-digalloyl-(-)-epigallocatechin exhibited a weaker inhibition of HeLa S3 cell proliferation than 3,5-digalloyl-(-)-epicatechin did. The DPPH radical scavenging activity of the synthesized compounds suggested that the galloyl-modified position and the number of phenolic hydroxyl groups on B-ring affected to the radical scavenging ability. In conclusion, we found that 3,5-digalloyl-(-)-epicatechin exhibited a superlative HeLa S3 cell proliferation inhibitory effect among the galloylated flavan-3-ol derivatives we synthesized and DPPH radical scavenging activity was affected by the galloyl-moiety-introduced position and the number of phenolic hydroxyl groups on the B-ring.