Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model.

doi:10.1021/acs.jmedchem.7b00637

Paper

Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model.

Published Jul 18, 2017 · G. Vignaroli, G. Iovenitti, C. Zamperini

Journal of medicinal chemistry

Q1 SJR score

28

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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.

In Vitro Study

Study Snapshot

Pyrazolo[3,4-d]pyrimidine prodrugs with improved aqueous solubility and enhanced pharmacokinetic and therapeutic properties show potential as promising anticancer agents in an orthotopic glioblastoma model.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model.

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References

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SI221 shows potential as a selective SRC family kinase inhibitor for glioblastoma treatment, with high metabolic stability and potential to cross the blood brain barrier.

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The optimized pyrazolo[3,4-d]pyrimidines show increased potency and in vivo activity against neuroblastoma, with compound 29 showing in vivo activity in a xenograft model.

Citations

Advances in pyrazolo[1,5-a]pyrimidines: synthesis and their role as protein kinase inhibitors in cancer treatment

Recent advances in pyrazolo[1,5-a]pyrimidine synthesis show promise for targeted cancer therapy, with EGFR-targeting derivatives showing promise in non-small cell lung cancer treatment and B-Raf and MEK kinase inhibitors in melanoma.

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Nanotechnology-based therapies show significant potential in treating colon cancer brain metastasis by minimizing systemic toxicity, enhancing therapeutic efficacy, and facilitating targeted drug delivery.

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The novel boron-conjugated SRC inhibitor combined with Proton Boron Capture Therapy shows potential in enhancing glioblastoma treatment with less damage to healthy tissue.

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The novel SI306 theranostic prodrug shows potential in improving glioblastoma treatment outcomes by combining therapeutic and diagnostic approaches through personalized medicine.

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Small molecules showing promising activity as tyrosine kinase inhibitors show promise in treating glioblastoma multiforme (GBM).

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Albumin-based drug delivery systems show potential in overcoming the blood-brain barrier to effectively treat brain cancer, particularly glioblastoma.

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SI388 is a potent Src inhibitor that affects cancer cell viability, tumorigenicity, and sensitivity to ionizing radiation in glioblastoma cellular models.