Semisynthetic Ursolic Acid Fluorolactone Derivatives Inhibit Growth with Induction of p21waf1 and Induce Apoptosis with Upregulation of NOXA and Downregulation of c‐FLIP in Cancer Cells

Abstract

A series of ursolic acid ((1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid) derivatives with a 12-fluoro-13,28β-lactone moiety were synthesized using the electrophilic fluorination reagent Selectfluor. The antiproliferative effects of these novel compounds were evaluated in AsPC-1 pancreatic cancer cells, and the structure-activity relationships (SARs) were evaluated. Of the compounds synthesized, ursolic acid derivatives carrying a heterocyclic ring, such as imidazole or methylimidazole, and cyanoenones were among the more potent inhibitors of AsPC-1 pancreatic cancer cell growth. 2-Cyano-3-oxo-12α-fluoro-urs-1-en-13,28β-olide, compound 20, was the most effective inhibitor with IC(50) values of 0.7, 0.9 and 1.8 μM in pancreatic cancer cell lines AsPC-1, MIA PaCa-2 and PANC-1, respectively. This compound also exhibited better antiproliferative activities against breast (MCF7), prostate (PC-3), hepatocellular (Hep G2) and lung (A549) cancer cell lines, with IC(50) values lower than 1 μM. The mechanism of action by which these compounds exert their biological effect was evaluated in AsPC-1 cells using the most potent inhibitor synthesized, compound 20. At 1 μM, the cell cycle arrested at the G1 phase with upregulation of p21(waf1). Apoptosis was induced at an inhibitor concentration of 8 μM with upregulation of NOXA and downregulation of c-FLIP. These data indicate that fluorolactone derivatives of ursolic acid have improved antiproliferative activity, acting through arrest of the cell cycle and induction of apoptosis.