Abstract
Betulinic acid (BA) is a potent triterpene, which has shown promising potential in cancer and HIV-1 treatment. Here, we report a synthesis and biological evaluation of 17 new compounds, including BODIPY labelled analogues derived from BA. The analogues terminated by amino moiety showed increased cytotoxicity (e.g., BA had on CCRF-CEM IC50 > 50 μM, amine 3 IC50 0.21 and amine 14 IC50 0.29). The cell-cycle arrest was evaluated and did not show general features for all the tested compounds. A fluorescence microscopy study of six derivatives revealed that only 4 and 6 were detected in living cells. These compounds were colocalized with the endoplasmic reticulum and mitochondria, indicating possible targets in these organelles. The study of anti-HIV-1 activity showed that 8, 10, 16, 17 and 18 have had IC50i > 10 μM. Only completely processed p24 CA was identified in the viruses formed in the presence of compounds 4 and 12. In the cases of 2, 8, 9, 10, 16, 17 and 18, we identified not fully processed p24 CA and p25 CA-SP1 protein. This observation suggests a similar mechanism of inhibition as described for bevirimat.
Highlights
Introduction published maps and institutional affilBetulinic acid (BA) is a natural pentacyclic triterpene of the lupane type (Figure 1).Despite its low solubility in aqueous solutions, this substance is gaining attention with its wide range of interesting biological activity
The thiomethyl group group is reactive towards amines
We examined proliferation markers and cell cycle profile of the sensitive CCRF-CEM cell line following a 24 h incubation with the derivatives (Table 2)
Summary
Despite its low solubility in aqueous solutions, this substance is gaining attention with its wide range of interesting biological activity. BA is often derivatized to increase solubility, enhance the therapeutic effect, and target the drug to the specific site of action [1]. BA shows a significant degree of selectivity for cytotoxicity against a variety of tumour cells mboxciteB2-biomedicines-1332342,B3-biomedicines-1332342,B4-biomedicines-1332342 and activity against HIV-1 [5]. One is the direct action of BA on the mitochondrial membrane, leading to an increase of outer membrane permeability, its depolarization and release of cytochrome c into the cytosol. It is responsible for triggering apoptosis [7].
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