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Cytotoxic heterocyclic triterpenoids derived from betulin and betulinic acid

2012; Elsevier BV; Volume: 20; Issue: 11 Linguagem: Inglês

10.1016/j.bmc.2012.03.066

1464-3391

Milan Urban, Martin Vlk, Petr Džubák, Marián Hajdúch, Jan Šarek,

Plant biochemistry and biosynthesis

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.