Abstract A23: Novel ursolic acid derivatives with potent antitumor activity

Abstract Cancer is the fourth leading cause of death worldwide, within pancreatic cancer is the fourth leading cause of cancer death and without effective medical therapy.1 Natural products provide a promising source for developing effective anticancer agents.2 Ursolic acid is a pentacyclic triterpenoid present in plants, vegetables, and fruits that has been found to have several biological activities, including antitumor activity.3 In order to improve the preexisting antitumor activity of ursolic acid, a panel of semisynthetic derivatives were prepared, characterized, and evaluated for the antiproliferative activities in several cancer cell lines. Ursolic acid was chemically modified by the introduction of heterocyclic rings in several points of the backbone structure and was found that modifications at C2 had improved activities against proliferation of pancreatic cancer cell lines, inducing apoptosis with upregulation of p53 and NOXA levels, and downregulation of XIAP levels. Fluor is a highly desirable atom, in key positions of active molecules can improve metabolic and chemical stability, membrane permeability and binding affinity.4 We have introduced fluor into the ring C of ursolic acid and a series of ursane-type fluor-derivatives were synthesized. The most potent derivative was 19-fold more active than ursolic acid to inhibit Aspc-1 cell growth and to arrest cell cycle at G1 phase with upregulation of p21waf1, and apoptosis at higher concentrations with upregulation of NOXA and downregulation of c-FLIP. These new semisynthetic derivatives of ursolic acid may have potential for drug discovery to treat cancer. Citation Format: Ana S. Leal, Jorge A.R. Salvador, Jing Yongkui. Novel ursolic acid derivatives with potent antitumor activity [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A23.