Synthesis and preliminary colon cancer chemoprevention evaluation of a novel prodrug of 4'-geranyloxy-ferulic acid, active principle of Acronychia baueri Schott

4'-Geranyloxy-ferulic acid is a prenyloxy-cinnamic acid isolated in 1966 from the bark of Acronychia baueri Schott, an Australian small tree belonging to the family of Rutaceae [1]. Although known for four decades, only in the last five years some of the pharmacological properties of this secondary metabolite and its synthetic derivatives began to be characterized and some ester derivatives of 4'-geranyloxy-ferulic acid showed interesting pharmacological properties as dietary cancer chemopreventive agents in rodents [2, 3]. In order to achieve a novel approach in the treatment of colon cancer by dietary administered drugs, we carried out the synthesis of a novel prodrug of 4'-geranyloxy-ferulic acid based on the incorporation of the latter into a peptide sequence of general formula X-Ala-Pro-COOH (4'-geranyloxy-feruloyl-L-alanyl-L-proline) structurally built to be hydrolized by intestinal angiotensin-converting enzyme (ACE) so reaching in high concentration the large bowel. The synthesis was accomplished in 7 steps employing commercially available ferulic acid as starting material and led to obtain the desired prodrug in 56.6% overall yield. Colon cancer was induced in rats by treatment with azoxymethane (AOM) and dextrane sodium sulphate (DSS) in the basal diet for 1 week. The prodrug was then administered in the diet for 19 weeks at two concentration levels, 0.01% and 0.05%. Preliminary biological evaluation on colonic tumors developed revealed that at both concentration 4'-geranyloxy-feruloyl-L-alanyl-L-proline was a powerful colon cancer chemopreventive agent with a reduction in cancer incidence of 51.9% (p<0.05) and 76.6% (p<0.01) respectively.

References: 1. Prager, R.H., Thregold, H.M. (1966), Aust. J. Chem. 19: 451. 2. Han, B.S. et al. (2001), Jpn. J. Cancer Res. 92: 404. 3. Tanaka, T. et al. (2003), Oncology 64: 166 and references cited herein.