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

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.

Effectiveness of traffic-related elements in tree bark and pollen abortion rates for assessing air pollution exposure on respiratory mortality rates.

The majority of epidemiological studies correlate the cardiorespiratory effects of air pollution exposure by considering the concentrations of pollutants measured from conventional monitoring networks. The conventional air quality monitoring methods are expensive, and their data are insufficient for providing good spatial resolution. We hypothesized that bioassays using plants could effectively determine pollutant gradients, thus helping to assess the risks associated with air pollution exposure. The study regions were determined from different prevalent respiratory death distributions in the Sao Paulo municipality. Samples of tree flower buds were collected from twelve sites in four regional districts. The genotoxic effects caused by air pollution were tested through a pollen abortion bioassay. Elements derived from vehicular traffic that accumulated in tree barks were determined using energy-dispersive X-ray fluorescence spectrometry (EDXRF). Mortality data were collected from the mortality information program of Sao Paulo City. Principal component analysis (PCA) was applied to the concentrations of elements accumulated in tree barks. Pearson correlation and exponential regression were performed considering the elements, pollen abortion rates and mortality data. PCA identified five factors, of which four represented elements related to vehicular traffic. The elements Al, S, Fe, Mn, Cu, and Zn showed a strong correlation with mortality rates (R2>0.87) and pollen abortion rates (R2>0.82). These results demonstrate that tree barks and pollen abortion rates allow for correlations between vehicular traffic emissions and associated outcomes such as genotoxic effects and mortality data.