Biological and Mechanistic Characterization of Novel Prodrugs of Green Tea Polyphenol Epigallocatechin Gallate Analogs in Human Leiomyoma Cell Lines.

Uterine fibroids (leiomyomas) are very common benign tumors grown on the smooth muscle layer of the uterus, present in up to 75% of reproductive-age women and causing significant morbidity in a subset of this population. Although the etiology and biology of uterine fibroids are unclear, strong evidence supports that cell proliferation, angiogenesis and fibrosis are involved in their formation and growth. Currently the only cure for uterine fibroids is hysterectomy; the available alternative therapies have limitations. Thus, there is an urgent need for developing a novel strategy for treating this condition. The green tea polyphenol epigallocatechin gallate (EGCG) inhibits the growth of uterine leiomyoma cells in vitro and in vivo, and the use of a green tea extract (containing 45% EGCG) has demonstrated clinical activity without side effects in women with symptomatic uterine fibroids. However, EGCG has a number of shortcomings, including low stability, poor bioavailability, and high metabolic transformations under physiological conditions, presenting challenges for its development as a therapeutic agent. We developed a prodrug of EGCG (Pro-EGCG or 1) which shows increased stability, bioavailability and biological activity in vivo as compared to EGCG. We also synthesized prodrugs of EGCG analogs, compounds 2a and 4a, in order to potentially reduce their susceptibility to methylation/inhibition by catechol-O-methyltransferase. Here, we determined the effect of EGCG, Pro-EGCG, and 2a and 4a on cultured human uterine leiomyoma cells, and found that 2a and 4a have potent antiproliferative, antiangiogenic, and antifibrotic activities. J. Cell. Biochem. 117: 2357-2369, 2016. © 2016 Wiley Periodicals, Inc.

Novel epigallocatechin gallate analogs as potential anticancer agents: a patent review (2009 - present).

INTRODUCTION: Over the past three years numerous patents and patent applications have been published relating to scientific advances in the use of the green tea polyphenol epigallocatechin gallate (EGCG) (the most abundant, and bioactive compound in green tea) and its analogs as anticancer agents. EGCG affects multiple molecular targets involved in cancer cell proliferation and survival; however, polyphenolic catechins, such as EGCG, generally exhibit poor oral bioavailability. Since the anticancer activity of polyphenols largely depends on their susceptibility to biotransformation reactions, numerous EGCG derivatives, analogs and prodrugs have been designed to improve the stability, bioavailability and anticancer potency of the native compound. AREAS COVERED: This review focuses on the applications of EGCG and its analogs, derivatives and prodrugs in the prevention and treatment of human cancers. A comprehensive description of patents related to EGCG and its derivatives, analogs and prodrugs and their uses as anticancer agents is included. EXPERT OPINION: EGCG targets multiple essential survival proteins and pathways in human cancer cells. Because it is unstable physiologically, numerous alterations to the EGCG molecule have been patented, either to improve the integrity of the native compound or to generate a more stable yet similarly efficacious molecule. EGCG and its derivatives, analogs and prodrugs could be developed into future drugs for chemoprevention, chemosensitization, radiosensitization and/or cancer interception.