Prodrugs of pyrazolo[3,4-d]pyrimidines: from library synthesis to evaluation as potential anticancer agents in an orthotopic glioblastoma model

Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth to be further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a-9a,e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4-4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated in this case to be a successful strategy for improving aqueous solubility of the parental drugs determining a positive impact also in their biological efficacy.