Synthesis and characterization of a novel Naphthalimide-Selenium based Temozolomide drug conjugate in glioma cells

Temozolomide (TMZ)² is the frontline chemotherapeutic drug against glioblastoma. As chemoresistance is a severe limitation of TMZ therapy, we aimed to synthesize a novel drug to improve its efficacy. This was achieved by conjugating TMZ with Naphthalimide (known DNA intercalator) via selenourea linkage (redox regulator). The synthesized Naphthalimide-selenourea-TMZ (Naph-Se-TMZ)³ exhibited heightened cell death in TMZ-sensitive and TMZ-resistant glioma cells compared to an equivalent dose of TMZ. Diminished cell viability was concomitant with heightened reactive oxygen species (ROS)⁴ levels in Naph-Se-TMZ treated cells. Docking simulations and in vitro studies attributed the improved cytotoxicity of Naph-Se-TMZ to its ability to inhibit HDAC1. A ROS-dependent decrease in HDAC1 expression and total HDAC activity was observed in Naph-Se-TMZ treated cells. We report the heightened cytotoxicity of synthesized novel Naph-Se-TMZ over TMZ in TMZ-resistant and TMZ-sensitive glioma cells through its ability to serve as a ROS generator and HDAC inhibitor. Importantly, TCGA dataset analysis indicating the association of heightened HDAC1 expression with poor prognosis and elevated antioxidant enzyme levels in glioma patients points towards the likely involvement of HDAC1 in protecting glioma cells from oxidative stress-induced damage. Taken together, our findings underscore the potential of Naph-Se-TMZ as a more effective therapeutic alternative to TMZ for glioblastoma treatment.