Novel polyphenols that inhibit colon cancer cell growth affecting cancer cell metabolisms

New series of polyphenols with a hydrophilic galloyl-based head and a hydrophobic N-acyl tail, linked through a serinol moiety, have been synthesized and tested against colon cancer cell growth. Our structure activity relationship studies revealed that galloyl moieties are essential for growth inhibition. Moreover, the length of the N-acyl chain is crucial for the activity. Introduction of a (Z) double bond in the acyl chain increased the anticancer properties. Our findings demonstrate that 16, the most potent compound within this series, has inhibitory effects on colon cancer cell growth and metabolism (glycolysis and mitochondrial respiration) at the same time that it activates 59AMP-activated kinase (AMPK) and induces apoptotic cell death. Based on these results, we propose that 16 might reprogram colon cancer cell metabolism through AMPK activation. This might lead to alterations on cancer cell bioenergy compromising cancer cell viability. Importantly, these antiproliferative and proapoptotic effects are selective for cancer cells. Accordingly, these results indicate that 16, with an unsaturated C18 chain, might be a useful prototype for the development of novel colon cancer cell growth inhibitors affecting cell metabolism.This work was supported by the Spanish Plan Nacional de Cooperación Público-Privada, Subprograma INNPACTO (IPT-2012-0213 060000, cofinanced by the FEDER program); the Spanish MINECO [Project SAF2015-64629-C2-1-R (MINECO/FEDER)]; AGL2016-76736-C3-3-R (MINECO/FEDER); and Regional government Comunidad de Madrid (P2013/ABI-2728, ALIBIRD-CM) and European Union Structural Funds. The European Social Fund (Youth Employment Operational Program 2014-2020) supports a contract in practices (to A.J.).Peer Reviewe