Glioblastoma (GBM) is the most common and aggressive malignant grade IV brain tumour and is one of the most difficult types of brain cancer to treat with a high incidence of resistance to traditionally used chemotherapeutics. Pyrazolopyrimidinones are fused nitrogen-containing heterocyclic systems which are a scaffold in several bioactive drugs and drug candidates. Here, a structure activity relationship (SAR) study was performed where 23 substituted pyrazolo[1,5-α]pyrimidinones were screened for cytotoxicity against the GBM U-251 MG cell line and the non-cancerous embryonic kidney HEK293 cell line to assess their potential as anti-glioblastoma agents capable of selectivity for cancer cells. Through analogue synthesis of preliminary HIT compounds with varied structural substituents, a lead compound, 22, has been identified, which proved capable of inducing significant GBM cell death while having a marginal cytotoxicity against the non-cancerous cells. The mode of cell death studies suggested that the structurally varied HIT compounds induced cell death through differential mechanisms including cell membrane permeabilization and mitochondria membrane depolarization dependent mechanisms such as necrosis or apoptosis. The results highlight the potential of pyrazolo[1,5-α]pyrimidinones derivatives as a novel anti-glioblastoma therapy, capable of selectively killing cancer cells. Furthermore pyrazolo[1,5-α]pyrimidinones provide a scaffold for further development of selective glioblastoma therapies.
Keywords: Cancer * Pyrazolo[1,5-α]pyrimidinones * Glioblastoma * Structure-activity relationships (SAR).
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