Betulinic Acid Decorated with Polar Groups and Blue Emitting BODIPY Dye: Synthesis, Cytotoxicity, Cell-Cycle Analysis and Anti-HIV Profiling

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.

Plant Secondary Metabolites Used for the Treatment of Diseases and Drug Development

“…This paper described the synthesis of betulinic acid derivatives, their cytotoxicity, cell-cycle analysis, and anti-HIV profiling. The results of this study suggest that betulinic acid has a similar mechanism of inhibition as described in bevirimat [4].…”

Cytotoxic and Anti-Inflammatory Triterpenoids in the Vines and Leaves of Momordica charantia

“…Therefore, in addition to lipophilicity, there are likely other factors that influence the bioactivity or cytotoxicity of these compounds. For example, MAPKs regulate mitochondrial metabolism [26], and some compounds were reported to target mitochondria for their cytotoxic or anti-inflammatory effects [24,27,28]. Thus, whether the triterpenoids reported in this study target mitochondria deserves to be addressed.…”

Semisynthetic Derivatives of Pentacyclic Triterpenes Bearing Heterocyclic Moieties with Therapeutic Potential

“…The anticancer effect was compared with BA and bevirimate, a BA-derivative with potent anti-HIV activity, which was abandoned in phase two clinical trials due to resistance acquisition. A SAR evaluation was performed on those derivatives that exhibited IC 50 values within the micromolar range ( Table 3 ) and revealed that BA-pyperazinyl derivatives induce slightly higher cytotoxic effects compared with BA-aminopropyl derivatives; in addition, the esterification of C3 with succinic acid or BODIPY-COOH diminished the overall cytotoxicity, thus suggesting that free C3 (BA 27) plays a key role in the occurrence of cytotoxic activity [ 65 ]. Although the study showed clearly superior cytotoxicity compared with BA and beviramat, the same effect was also exerted against normal cells, thus limiting their development as therapeutic compounds.…”