title: Cytotoxic heterocyclic triterpenoids derived from betulin and betulinic acid.
abstract: The aim of this work was to synthesize a set of heterocyclic derivatives of lupane, lup-20(29)-ene, and 18α-oleanane, and to investigate their cytotoxic activities. Some of those heterocycles were previously known in the oleanane (allobetulin) group; however, to our knowledge the syntheses and biological activities of lupane heterocycles have not been reported before. Starting from betulin (1) and betulinic acid (2), we prepared 3-oxo compounds and 2-bromo-3-oxo compounds 3-10, 2-hydroxymethylene-3-oxo compounds 11-13 and β-oxo esters 14-16. Condensation of these intermediates with hydrazine, phenylhydrazine, hydroxylamine, or thiourea yielded the pyrazole and phenylpyrazole derivatives 17-22, pyrazolones 23-25, isoxazoles 26 and 27, and thiazoles 28-31. Fifteen compounds (14-16, 18-25, and 29-32) have not been reported before. The cytotoxicity was measured using panel of seven cancer cell lines with/without MDR phenotype and non tumor MRC-5 and BJ fibroblasts. The preferential cytotoxicity to cancer cell lines, particularly to hematological tumors was observed, the bromo acids 5, 6 showed highest activity and selectivity against tumor cells.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Urban
authors.forename: Martin
authors.initials: M
authors.lastname: Vlk
authors.forename: Petr
authors.initials: P
authors.lastname: Dzubak
authors.forename: Marian
authors.initials: M
authors.lastname: Hajduch
authors.forename: Jan
authors.initials: J
authors.lastname: Sarek
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D053978:Pentacyclic Triterpenes; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C413246:oleanane; C480546:lupane; D009828:Oleanolic Acid; C002503:betulin; D000094062:Betulinic Acid