Abstract
Glioblastoma (GBM) is the most common form of malignant primary brain tumor and is one of the most lethal cancers. The difficulty in treating GBM stems from its highly developed mechanisms of drug resistance. Our research team has recently identified the fungal secondary metabolite ophiobolin A (OpA) as an agent with significant activity against drug-resistant GBM cells. However, the OpA's mode of action is likely based on covalent modification of its intracellular target(s) and thus possible off-target reactivity needs to be addressed. This work involves the investigation of an acid-sensitive OpA analogue approach that exploits the elevated acidity of the GBM microenvironment to enhance the selectivity for tumor targeting. This project identified analogues that showed selectivity at killing GBM cells grown in cultures at reduced pH compared to those maintained under normal neutral conditions. These studies are expected to facilitate the development of OpA as an anti-GBM agent by investigating its potential use in an acid-sensitive analogue form with enhanced selectivity for tumor targeting.