title: Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives.
abstract: Betulin, a naturally occurring abundant triterpene is converted in four steps to 3,28-di-O-acetyllupa-12,18-diene. When various 4-substituted urazoles were oxidized to the corresponding urazines with iodobenzene diacetate in the presence of 3,28-di-O-acetyllupa-12,18-diene, new heterocyclic betulin derivatives were produced. These betulin derivatives were examined in a microplate assay at 50 microM for their ability to inhibit the growth of Leishmania donovani axenic amastigotes, a species that causes the fatal visceral leishmaniasis. GI(50) (concentration for 50% growth inhibition) values of the most effective compounds were determined and their cytotoxicity on the human macrophage cell line THP-1 evaluated. The anti-leishmanial activity on L. donovani amastigotes growing in macrophages was also examined. The heterocycloadduct between 3,28-di-O-acetyllupa-12,18-diene and 4-methylurazine was the most effective derivative with an GI(50)=8.9 microM against L. donovani amastigotes.
authors.affiliation: Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Alakurtti
authors.forename: Tuomo
authors.initials: T
authors.lastname: Heiska
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kiriazis
authors.forename: Nina
authors.initials: N
authors.lastname: Sacerdoti-Sierra
authors.forename: Charles L
authors.initials: CL
authors.lastname: Jaffe
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D000981:Antiprotozoal Agents; D006571:Heterocyclic Compounds; D014315:Triterpenes; C002503:betulin; D000094062:Betulinic Acid