title: Urea derivates of ursolic, oleanolic and maslinic acid induce apoptosis and are selective cytotoxic for several human tumor cell lines.
abstract: 2,3-Di-O-acetyl-maslinic acid benzylamide (5) has previously been shown to possess high cytotoxicity for a variety of human tumor cell lines while being of low cytotoxicity to non-malignant cells. Structural modifications performed on 5 revealed that the presence of these acetyl groups in 5 and the presence of (2β,3β)-configurated centers seems necessary for obtaining high cytotoxicity combined with best selectivity between malignant cells and non-malignant mouse fibroblasts. Compounds carrying an ursane skeleton showed weaker cytotoxicity than their oleanane derived analogs. In addition, the benzylamide function in compound 5 should be replaced by a phenylurea moiety to gain better cytotoxicity while retaining and improving the selectivity. Thus, maslinic acid derived N-[2β,3β-di-O-acetyl-17β-amino-28-norolean-12-en-17-yl]phenylurea (45) gave best results showing EC50 = 0.9 μM (for A2780 ovarian cancer cells) with EC50 > 120 μM for fibroblasts (NIH 3T3) and triggered apoptosis while caspase-3 was not activated by this compound.
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D-06120, Halle, Saale, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Sommerwerk
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D-06120, Halle, Saale, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Heller
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D-06120, Halle, Saale, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kuhfs
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D-06120, Halle, Saale, Germany. Electronic address: rene.csuk@chemie.uni-halle.de.
authors.forename: René
authors.initials: R
authors.lastname: Csuk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009828:Oleanolic Acid / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D000097245:Ursolic Acid
chemical_list: D009828:Oleanolic Acid; D014315:Triterpenes; D000097245:Ursolic Acid; C412811:maslinic acid
keywords: Apoptosis; Maslinic acid; Oleanolic acid; SRB assay; Tumor cells; Ursolic acid