Ursolic acid 1  is a pentacyclic triterpenoid present in fruits and vegetables, and has been found to have some antitumor and chemopreventive activities in vitro and in vivo models of cancer. Fluor is a highly desirable atom, and added in to key positions of active molecules can improve metabolic and chemical stability, membrane permeability and binding affinity. We introduced a fluor into the ring C of ursolic acid 1  and synthesized a series of ursane fluorolactone derivatives with esthers, carbamates or a carbonyl group at position C3, and a cyano group at position C2. Imidazole, methylimidazole and triazole rings in conjugation with an unsaturated a,� ketone in ring A of the ursane fluorolactone backbone were also synthesized. The antiproliferative effects of these new compounds were tested in a pancreatic cancer cell line Aspc-1, and the structure-activity relationship (SAR) was analyzed. The best compound was found to have improved antiproliferative activity 19-fold over ursolic acid 1  . Mechanistic studies revealed that this compound arrested cell cycle at the G1 phase with 1�M through increase of p21waf1, and induced apoptosis at 8 mM with the upregulation of NOXA and the downregulation of c-FLIP. These data suggest that fluorolactone derivatives of ursolic acid 1  inhibit cancer cell growth through novel pathways.  Acknowledgment:  Ana S. Leal is supported by Funda��o para a Ci�ncia e Tecnologia (SFRH/BD/41566/2007). Jorge A.R. Salvador is supported by Universidade de Coimbra. Yongkui Jing is supported by The Samuel Waxman Cancer Research Foundation.

New fluoro-derivatives of ursolic acid with improved antitumor activity

244th National Meeting (2012)

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