Design, Synthesis and Biological Evaluation of Betulinic Acid Derivatives as New Antitumor Agents for Leukemia
Autor: | Fernanda Waechter, Andréia Buffon, Diogo André Pilger, Simone Cristina Baggio Gnoatto, Gloria Narjara Santos da Silva, Julia Biz Willig, Aline Rigon Zimmer, Daniela Barreto Trivella, Cristiane Bernardes de Oliveira, Bruna Domingues Vieira |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Antineoplastic Agents Pharmacology 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship hemic and lymphatic diseases Betulinic acid Leukemia Myelogenous Chronic BCR-ABL Positive medicine Humans Betulinic Acid Spectrum Analysis Imatinib Biological activity Proteasome complex Triptolide Triterpenes HaCaT 030104 developmental biology Biochemistry chemistry Drug Design Proteasome inhibitor Molecular Medicine Drug Screening Assays Antitumor K562 Cells Pentacyclic Triterpenes medicine.drug K562 cells |
Zdroj: | Anti-cancer agents in medicinal chemistry. 17(13) |
ISSN: | 1875-5992 |
Popis: | Background 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. Objective 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. Method 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. Result 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. Conclusion Proteasome inhibition assays suggest that proteasome is the main target for betulinic acid and its derivatives. |
Databáze: | OpenAIRE |
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