title: Design, Synthesis and Biological Evaluation of Betulinic Acid Derivatives as New Antitumor Agents for Leukemia.
abstract: Chronic myeloid leukemia (CML) is currently treated with imatinib, a Bcr-Abl inhibitor. However, resistance to this drug usually develops over time. Triptolide, a diterpenoid triepoxide, has been shown active against CML cells resistant to imatinib, acting mainly on the level of Bcr-Abl transcription inhibition.
  
  
  
  Here, we used the triterpene betulinic acid, a known proteasome inhibitor with potential antileukemic activity, as a scaffold for the generation of analogues with predicted triptolide biological activity.
  
  
  
  Betulinic acid derivatives were designed based on the structure-activity relationship of triptolide and evaluated for their cytotoxic effects in CML cells, lymphocytes and human keratinocytes (HaCaT), as well as against the proteasome complex. The main modification performed on betulinic acid was fluorination at C-28 and epoxidation, both of which are responsible for enhancing activity of triptolide. A total of 10 compounds were obtained: 6 previously described and 4 novel compounds. The cytotoxic activity over a CML cell line (K562) was assessed using flow cytometry and compared to lymphocytes and HaCaT.
  
  
  
  The results show that betulinic acid was the most cytotoxic compound against CML cells, showing a good selectivity index for cancer over normal cells. The most important trend for the activity in betulinic acid derivatives is the presence of a free hydroxyl group at C-3 and a carboxyl group at C-28. Results also indicated that the epoxide is important for enhancing the activity, while modification at C-28 worsens the activity.
  
  
  
  Proteasome inhibition assays suggest that proteasome is the main target for betulinic acid and its derivatives.
authors.affiliation: Laboratorio de Fitoquimica e Sintese Organica, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Waechter
authors.affiliation: Laboratorio de Fitoquimica e Sintese Organica, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Gloria N S
authors.initials: GNS
authors.lastname: da Silva
authors.affiliation: Laboratorio de Analises Bioquimicas e Citologicas, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Julia B
authors.initials: JB
authors.lastname: Willig
authors.affiliation: Laboratorio de Fitoquimica e Sintese Organica, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Cristiane B
authors.initials: CB
authors.lastname: de Oliveira
authors.affiliation: Laboratorio Nacional de Biociencias, Centro Nacional de Pesquisa em Energia e Materiais, Rua Giuseppe Maximo Scolfaro, 10000, Campinas, 13083-970. Brazil.
authors.forename: Bruna D
authors.initials: BD
authors.lastname: Vieira
authors.affiliation: Laboratorio Nacional de Biociencias, Centro Nacional de Pesquisa em Energia e Materiais, Rua Giuseppe Maximo Scolfaro, 10000, Campinas, 13083-970. Brazil.
authors.forename: Daniela B B
authors.initials: DBB
authors.lastname: Trivella
authors.affiliation: Laboratorio de Fitoquimica e Sintese Organica, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Aline R
authors.initials: AR
authors.lastname: Zimmer
authors.affiliation: Laboratorio de Analises Bioquimicas e Citologicas, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Andreia
authors.initials: A
authors.lastname: Buffon
authors.affiliation: Laboratorio de Analises Bioquimicas e Citologicas, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Diogo A
authors.initials: DA
authors.lastname: Pilger
authors.affiliation: Laboratorio de Fitoquimica e Sintese Organica, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752, Porto Alegre, 90610-000. Brazil.
authors.forename: Simone C B
authors.initials: SCB
authors.lastname: Gnoatto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D053978:Pentacyclic Triterpenes; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid
keywords: Betulinic acid; cancer chemotherapy; chronic myeloid leukemia; epoxidation; fluorination; proteasome inhibition; triptolide