title: Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid.
abstract: A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2 b) methyl 2-bromobetulonate (3 b), 2-bromooleanonic acid (5 b), and 2-thiocyanooleanonic acid (5 c) were best, with IC50values less than 10 μm against CCRF-CEM cells (e.g., 3 b: IC50=2.9 μm) as well as 2'-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC50=9.7 μm) and 2'-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 k, IC50=11.4 μm). Compound 5 c leads to the accumulation of cells in the G2phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1×IC50. The G2/M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5 c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3 b) and methyl 2-thiocyanometulonate (3 c) were found to inhibit nucleic acid synthesis only at 5×IC50. We assume that in 3 b and 3 c (unlike in 5 c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1×IC50or lower concentration.
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46, Olomouc, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Borkova
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46, Olomouc, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Adamek
authors.affiliation: Department of Chemistry of Natural Compounds, Faculty of Science, University of Chemistry and Technology, Technicka 5, 166 28, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Kalina
authors.affiliation: Department of Chemistry of Natural Compounds, Faculty of Science, University of Chemistry and Technology, Technicka 5, 166 28, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Drašar
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779 00, Olomouc, Czech Republic.
authors.forename: Petr
authors.identifier: 0000-0002-3098-5969
authors.initials: P
authors.lastname: Dzubak
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779 00, Olomouc, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Gurska
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779 00, Olomouc, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Rehulka
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779 00, Olomouc, Czech Republic.
authors.forename: Marian
authors.initials: M
authors.lastname: Hajduch
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779 00, Olomouc, Czech Republic.
authors.forename: Milan
authors.identifier: 0000-0002-8249-028X
authors.initials: M
authors.lastname: Urban
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779 00, Olomouc, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Sarek
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014315:Triterpenes / Q000737:chemistry*; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; D009828:Oleanolic Acid; D013844:Thiazoles; D014315:Triterpenes; C118308:betulonic acid; D000094062:Betulinic Acid; C450739:oleanonic acid
keywords: cell cycle; cytotoxicity; heterocycles; thiazoles; triterpenes