Catechin prodrugs and analogs: a new array of chemical entities with improved pharmacological and pharmacokinetic properties.

Extensive research on tea catechins, mainly (-)-epigallocatechin gallate, has shown numerous health promoting effects. However, various clinical studies demonstrated several issues associated with tea catechins which account for their poor systemic bioavailability. In order to improve pharmacological activity and bioavailability of natural tea catechins, two major strategies have been adopted to date which include synthesizing catechin analogs/prodrugs and the development of novel drug delivery systems. In this review, we provide a detailed account of novel synthetic analogs/prodrugs as well as novel drug delivery approaches used for natural tea catechins to make them therapeutically potent drug-like molecules.

Synthesis and evaluation of antioxidant-s-(+)-Ibuprofen hybrids as gastro sparing NSAIDs.

Ibuprofen is one of the most popular NSAIDs for the last three decades but also known for its gastrointestinal side effects similar to other NSAIDs. To overcome this problem, we have designed and synthesized ibuprofen - antioxidant (thymol, guaiacol, eugenol, and menthol) hybrids (6-13) with and without spacer as gastro sparing agents. The hybrids have been found to be chemically stable, biolabile and exhibited retention of anti-inflammatory and analgesic activity with significant reduced ulcerogenicity as compared to the ibuprofen and ibuprofen + antioxidant physical mixture. The absence of ulcerogenicity may be attributed to antioxidants and improved physicochemical properties of these hybrid molecules.

Potential O-acyl-substituted (-)-Epicatechin gallate prodrugs as inhibitors of DMBA/TPA-induced squamous cell carcinoma of skin in Swiss albino mice.

(-)-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.

Design, semisynthesis, and evaluation of O-acyl derivatives of (-)-epigallocatechin-3-gallate as antitumor agents.

UNLABELLED: The partially purified catechin fraction isolated from green tea extract was treated with a variety of acylating agents (acyl anhydrides/chloride) to obtain (-)-epigallocatechin-3-gallate (EGCG) O-acyl derivatives in 20-25.4% yields. The (-)-EGCG O-acyl derivatives were characterized by physical data and spectral studies. These compounds were evaluated for their antitumor activity by use of a two-stage carcinogenesis model in 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)--induced cancer in Swiss albino mice. The study showed that there was a significant decrease in the antitumor activity with the increase in size and branching of the chain length of acyl groups. The results indicated that these O-acyl derivatives of (-)-EGCG have the potential to be developed as cancer chemopreventive agents. KEYWORDS: Green tea; catechins; (-)-EGCG O-acyl derivatives; antitumor activity.