Synthesis of putative ASIC3 channel activators targeted against glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer, characterized by high proliferation and infiltration, and remains incurable. Acid-Sensing Ion Channels (ASICs) are proton-gated cation channels expressed in various tumors and linked to increased cell migration and proliferation. Notably, the ASIC3 isoform, typically found in the peripheral nervous system (PNS) and absent in the central nervous system (CNS), is enriched in human GBM cancer stem cells (CSCs) but poorly expressed in the healthy human brain, making it a potential novel therapeutic target to control GBM CSC growth.1 In vitro studies demonstrated that 2-guanidine-4-methylquinazoline (GMQ) significantly inhibited GBM CSCs growth, showing greater potency than the standard GBM drug, temozolomide (TMZ), and displaying a good safety profile on non-tumoral brain cells.2 The present study focuses on the design and synthesis of novel GMQ-like scaffolds targeting GBM, with enhanced blood-brain barrier (BBB) permeability with respect to a highly basic / charged guanidine. The latter moiety was thus replaced with a BBB-compliant guanylhydrazone surrogate (pKa 7-9), preserving bioactivity while improving CNS exposure. Furthermore, two focused libraries of substituted 2-methylquinazolines were synthesized, bearing the guanylhydrazone functionality either at the C-2 or C-4 position, depending on the adopted synthetic route. In vitro biological evaluation demonstrated significant activity for several analogues, reinforcing the therapeutic potential of this chemotype as a viable approach in the development of new treatments for glioblastoma.