Semisynthetic ursolic acid fluorolactone derivatives inhibit growth with induction of p21(waf1) and induce apoptosis with upregulation of NOXA and downregulation of c-FLIP in cancer cells.
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.
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Poló das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
Ana S
AS
Leal
Rui
R
Wang
Jorge A R
JA
Salvador
Yongkui
Y
Jing
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D054879:Halogenation; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000097245:Ursolic Acid
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007783:Lactones; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; D000097245:Ursolic Acid; C493956:CDKN1A protein, human; C498702:PMAIP1 protein, human