Abstract
Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being 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-8a and 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 24 h 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 to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Blood-Brain Barrier / metabolism
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Brain Neoplasms / drug therapy*
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Glioblastoma / drug therapy*
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Humans
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Male
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Membranes, Artificial
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Mice, Inbred C57BL
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Mice, Nude
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Microsomes, Liver / metabolism
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Prodrugs / chemical synthesis
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Prodrugs / chemistry*
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Prodrugs / pharmacology
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology
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Solubility
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Structure-Activity Relationship
Substances
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2-(4-methylpiperazin-1-yl)ethyl 6-(2-morpholinoethylthio)-1-(2-chloro-2-phenylethyl)-1H-pyrazolo(3,4-d)pyrimidin-4-yl 3-bromophenylcarbamate
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Antineoplastic Agents
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Membranes, Artificial
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Prodrugs
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Small Molecule Libraries