| abstract |
A novel synthetic method that provides access to previously undeveloped functions at the C8 position of imidazotetrazine. Through the synthesis and evaluation of a set of compounds having various aqueous stability (0.5 to 40 hours), a predictive model for the imidazotetrazine hydrolysis stability based on the Hammett constant of the C8 substituent was derived. Promising compounds with activity against a panel of GBM cell lines, adequate hydrolysis and metabolic stability, and dramatically increased brain-serum ratio compared to TMZ were identified, lowering the hematologic toxicity profile and superior activity against TMZ in the GBM mouse model. Show. |