Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Author(s):
Waechter, Fernanda [1] ; da Silva, Gloria N. S. [1] ; Willig, Julia B. [2] ; de Oliveira, Cristiane B. [1] ; Vieira, Bruna D. [3] ; Trivella, Daniela B. B. [3] ; Zimmer, Aline R. [1] ; Buffon, Andreia [2] ; Pilger, Diogo A. [2] ; Gnoatto, Simone C. B. [1]
Total Authors: 10
Affiliation:
[1] Univ Fed Rio Grande do Sul, Fac Farm, Lab Fitoquim & Sintese Organ, Ave Ipiranga 2752, BR-90610000 Porto Alegre, RS - Brazil
[2] Univ Fed Rio Grande do Sul, Fac Farm, Lab Anal Bioquim & Citol, Ave Ipiranga 2752, BR-90610000 Porto Alegre, RS - Brazil
[3] Ctr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias, Rua Giuseppe Maximo Scolfaro 10000, BR-13083970 Campinas, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY; v. 17, n. 13, p. 1777-1785, 2017.
Web of Science Citations: 3
Abstract

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. (AU)

FAPESP's process: 14/10753-9 - Bioprospecting and rational design for the discovery of next generation proteasome inhibitors
Grantee:Daniela Barretto Barbosa Trivella
Support Opportunities: Regular Research Grants