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ChemMedChem. 2019 Nov 20;14(22):1933-1939. doi: 10.1002/cmdc.201900481. Epub 2019 Nov 7.

Oxidative Cyclization-Induced Activation of a Phosphoinositide 3-Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics.

Author information

1
Figueroa, Prof. Dr. Edward. J. Merino* Department of Chemistry, McMicken College of Arts and Sciences, University of Cincinnati, Cincinnati, OH 45221, USA.
2
James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45221, USA.
3
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45221, USA.

Abstract

In this work, we designed a prodrug that reacts with cellular oxidative equivalents leading to ether cleavage and cyclization to release an active phosphatidylinositol 3-kinase (PI3K) inhibitor. We show that the compound reduces affinity for PI3KA relative to the PI3K inhibitor, is slow to intercellularly oxidize, and is resistant to liver microsomes. We observed modest activity in untreated acute myeloid leukemia cells and 14-fold selectivity relative to non-cancerous cells. The cellular activity of the compound can be modulated by the addition of antioxidants or oxidants, indicating the compound activity is sensitive to cellular reactive oxygen species (ROS) state. Co-treatment with cytosine arabinoside or doxorubicin was used to activate the compound inside cells. We observed strong synergistic activity specifically in acute myeloid leukemia (AML) cancer cells with an increase in selective anticancer activity of up to 90-fold. Thus, these new self-cyclizing compounds can be used to increase the selectivity of anticancer agents.

KEYWORDS:

oxidative cyclization; phosphoinositide 3-kinase inhibitors; prodrugs; reactive oxygen species; synergy effects

PMID:
31696673
DOI:
10.1002/cmdc.201900481

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