UC San Diego

According to the World Health Organization, almost 10 million people worldwide died of cancer in 2020, a number that is expected to rise to over 16 million annually by 2040. As a result, there is a pressing need for drugs that effectively eliminate cancer in new and innovative ways. This dissertation addresses this challenge by first discussing an improved method for the extraction and purification of gambogic acid (GBA), a highly cytotoxic compound that is part of a family of synthetic and natural products collectively known as caged Garcinia xanthones (CGXs) . We next identify novel CGXs with improved cytotoxicity in several breast cancer cell lines. Lastly, we identified novel drug leads for proteins that have not been previously identified as amenable to pharmaceutical modulation. Specifically, we developed an in vitro model that identified new CGXs that can bind to the surface of the mitochondrial NEET protein MiNT and modulate the release of its Fe-S clusters. We identified an improved method for the expression and purification of MiNT, and by utilizing various spectroscopic methods, we measured binding constants of CGXs to MiNT and determined that they have a stabilizing effect on its Fe-S clusters as seen in spectroscopic measurements of their decay. In addition, we identified structural changes of MiNT that occur due to binding of xanthone ligands and their contribution to the stability of MiNT Fe-S clusters. Taken together, our results demonstrate that CGXs are highly cytotoxic in numerous cancer cell lines, and that one of their protein targets, the Fe-S protein MiNT, is a novel promising target for anticancer pharmaceutical development, specifically with CGXs.