Identification of imidazoquinoline derivatives as potent antiglioma agents.

Glioblastoma Multiforme (GBM) is a highly fatal disease and new chemotherapeutic agents are desperately needed to treat GBM patients. With the aim of identifying new antiglioma agents we screened the UC DDC library for compounds structurally related to the antiglioma lead molecule compound 1 (SP-6-27) and clinically used compound 2 (Azixa). We identified imidazoquinoline analog 3 (S-94403) as initial hit from the first screen which included the different heterocyclic sets of 15 compounds. Based on the initial hit 3 (S-94403), a second search was performed to explore the structure activity relationship (SAR) study on imidazoquinolines. Our SAR revealed that a N-phenyl with EDGs/EWGs at C9 position, a methyl group at C7 position and an aryl or hetero-aryl groups at C2 position essential for the anticancer activity. These two consecutive screenings have identified the compounds S-94403 (IC50 = 0.625 µM) and S-98950 (IC50 = 1.04 µM) as the most potent imidazoquinoline-based antiglioma agents.