Synthesis and Antitumor Activity of Ellagic Acid Peracetate

Abstract

Ellagic acid (1) was synthesized for the first time from methyl gallate through 3-pentagalloylglucose (α-PGG), and ellagic acid peracetate (3,4,3′,4′-tetra-O-acetylellagic acid, 2) was derived from 1 by acetylation. Oral administration of 2 suppressed melanoma growth significantly in C7BL/6 immunocompetent mice without having any effect on natural killer (NK) cell activity. Comparison of the immunoenhancing activities of 1 and 2 indicated that the latter compound increased white blood cell quantities in peripheral blood and immune cells enriched from the bone marrow and liver of mice. Therefore, both the antitumor efficacy and the immunity enhancement by 2 were greater than those by 1. In addition, on oral administration neither 1 nor 2 resulted in whole body, liver, or spleen weight changes of normal, tumor-free mice, indicating that these compounds are potentially non-toxic to mice. It was shown that ellagic acid peracetate (2) inhibits B16 melanoma cell growth in vitro, and induces B16 cell apoptosis, corresponding to BCL-2 down-regulation. Collectively, the present data imply that 2 can suppress tumor growth by enhancing mouse immunity and inducing tumor cell apoptosis without apparent side effects.

Potent Cytotoxic Arylnaphthalene Lignan Lactones from Phyllanthus poilanei

“… 47 After HT-29 cells were treated with compound 1 or etoposide at different concentrations, annexin V flow cytometry was performed following a previous protocol. 48 Treatment of HT-29 cells with 1 or 5 μM phyllanthusmin D ( 1 ) for 72 h resulted in 28.2% or 30.3% of HT-29 cells undergoing early apoptosis, respectively, while the analogous values for the vehicle control or 1 or 5 μM etoposide treatments were 3.9%, 12.9%, and 12.5%, respectively (Figure 5 ). Also, 1 induced 27.3% (at 1 μM) and 38.0% (at 5 μM) HT-29 cell apoptosis at the late stage, while the vehicle control or 1 or 5 μM etoposide treatments induced 8.6%, 19.8%, or 25.3% HT-29 cell apoptosis at this stage, respectively (Figure 5 ).…”

Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid

“…In vivo oral administration of EA-peracetate significantly suppressed melanoma growth in C57BL/6 mice and increased white blood cell number in peripheral blood. Both the antitumor efficacy and immune stimulation exerted by EA-peracetate in an in vivo model of melanoma were greater as compared to those induced by EA, suggesting that appropriate chemical modifications might enhance EA antitumor potential [ 89 ]. Finally, by using chitosan films as local carrier of EA, Kim and collaborators demonstrated that films containing 0.5 and 1% of the polyphenolic compound ( w / v ) exerted potent antiproliferative and apoptotic effects in human melanoma WM115 cells [ 90 ].…”

Potent cytotoxic arylnaphthalene lignan lactones from Phyllanthus poilanei

“…47 After HT-29 cells were treated with compound 1 or etoposide at different concentrations, annexin V flow cytometry was performed following a previous protocol. 48 Treatment of HT-29 cells with 1 or 5 μM phyllanthusmin D (1) for 72 h resulted in 28.2% or 30.3% of HT-29 cells undergoing early apoptosis, respectively, while the analogous values for the vehicle control or 1 or 5 μM etoposide treatments were 3.9%, 12.9%, and 12.5%, respectively ( Figure 5). Also, 1 induced 27.3% (at 1 μM) and 38.0% (at 5 μM) HT-29 cell apoptosis at the late stage, while the vehicle control or 1 or 5 μM etoposide treatments induced 8.6%, 19.8%, or 25.3% HT-29 cell apoptosis at this stage, respectively ( Figure 5).…”

“…Annexin V Staining Method. As described in previous studies, 48 HT-29 cells were treated with the vehicle control or etoposide (1 or 5 μM) or 1 (1 or 5 μM) for 72 h. The cells were washed with annexin V binding buffer, centrifuged at 300g for 10 min, and suspended (1 × 10 6 ) in 100 μL of 1× annexin V binding buffer. Then, 10 μL of annexin V-APC was added to the suspension.…”