Biosynthesis of Progesterone Glycosides as Potential Anti-Cancer Agents 

Ying-Chu Chou (周映竹) 1, Feng-Pai Chou 2,Tung-Kung Wu *

1 Department of Biological science and Technology, National Yang Ming Chiao Tung University

Glycosylation of natural products has proven to be an emerging approach to enhance physiochemical and biological activities and develop new drugs. Progesterone (PG) is a steroid hormone, mainly synthesized and secreted by the ovaries, placenta, testes, adrenal cortex. It can regulate women’s menstrual cycle, pregnancy and lactation, and sperm development and function. Recent studies have shown that 3α-hydroxyprogesterone, a metabolite of PG in breast tissue, is a potential drug for the treatment of breast cancer. In addition, 20α-hydroxyprogesterone and nomegestrol acetate (NOMAC), inhibitors of aromatase (CYP19A1), play a crucial role in breast cancer. In this study, we synthesized several rare configuration PG-3O-b-glycosides and PG-20O-β-Glycosides using an enzymatic one-pot system and evaluated their anti-cancer effects on MCF-7 breast cancer cells. The one-pot system consists of Bifidobacterium longum N-acetylhexosamine 1-kinase (NahK), Bifidobacterium longum UDP-sugar pyrophosphorylase (BLUSP) and Pasteurella multocida inorganic pyrophosphatase (PmPpA) for UDP-monosaccharide synthesis, HP0421 or Bs-Yjic as glycosyltransferase for glycosylation reactions. The obtained compounds were characterized structurally by ESI-MS and NMR. Furthermore, cytotoxicity assessments of purified compounds on MCF-7 cells showed that PG-3O-β-Glycosides(8-9) and PG-20O-β-Glycoside(10-11) exhibited significant dose-dependent cytotoxic activity against MCF-7 cells with IC50 values ranging from 55.18 to 59.34 μM.