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Potential O ‐Acyl‐Substituted (−)‐Epicatechin Gallate Prodrugs as Inhibitors of DMBA/TPA‐Induced Squamous Cell Carcinoma of Skin in Swiss Albino Mice
Author(s) -
Vyas Sandeep,
Ma Benu,
Vir Singh Tej,
Dev Sharma Pritam,
Sharma Manu
Publication year - 2011
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201000219
Subject(s) - chemistry , dmba , prodrug , bioavailability , gallate , stereochemistry , catechin , polyphenol , pharmacology , biochemistry , carcinogenesis , antioxidant , nuclear chemistry , medicine , gene
(−)‐Epicatechin‐3‐gallate ( 1 ) is one of the principal catechins of green tea and exhibits cancer‐preventive activities in various animal models. However, this compound is unstable in neutral or alkaline medium and, therefore, has a poor bioavailability. To improve its stability, O ‐acyl derivatives of 1 were prepared by isolating the partially purified tea catechin fraction from green tea extract and treating it with a variety of acylating agents. The resulting derivatives, compounds 2 – 6 , were screened for their antitumor potential against 7,12‐dimethylbenz[ a ]anthracene (DMBA)/12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced squamous cell carcinogenesis of skin in mice. The results showed that the antitumor activity decreased with the increase in size of the chain length of the acyl groups, i.e. , from compound 2 , derivative with an Ac group, to compound 6 , possessing a valeryl group. Moreover, the C 4 derivative with a branched acyl chain, 5 , had a lower activity than the linear C 4 derivative 4 . This reduction in the inhibitory activity may be due to the steric hindrance by the two Me groups. Moreover, significant increases in the protein levels analyzed by ELISA of c‐Jun, p65, and p53 were observed in the skin of DMBA/TPA treated mice, whereas mice treated with 2 and DMBA/TPA had a similar expression of these transcription factors than the control mice. The prodrug potential of the O ‐acyl derivatives 2 – 6 showed that they were adequately stable to be absorbed intact from the intestine, more stable at gastric pH, and suitable for oral administration.