Design, Synthesis, and Biological Evaluation of Betulinic Acid Derivatives as New Antitumor Agents for Leukemia

(E-pub Ahead of Print)

Author(s): Fernanda Waechter, Gloria Santos Silva, Julia Willig, Cristiane Bernardes de Oliveira, Bruna Domingues Vieira, Daniela Barreto Trivella, Aline Rigon Zimmer, Andréia Buffon, Diogo André Pilger, Simone Gnoatto*.

Journal Name:Anti-Cancer Agents in Medicinal Chemistry

Volume 17 , 2017


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 activity, while modification at C-28 worsens activity. Proteasome inhibition assays suggest the proteasome is the main target for betulinic acid and its derivatives.

Keywords: Betulinic acid, cancer chemotherapy, triptolide, chronic myeloid leukemia, fluorination, epoxidation, proteasome inhibition

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Article Details

Year: 2017
(E-pub Ahead of Print)
DOI: 10.2174/1871521409666170412143638
Price: $95