Title: Oxidative Cyclization-Induced Activation of a Phosphoinositide 3-Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics.
Authors: Zhu, Haizhou; Mishra, Rosalin; Yuan, Long; Abdul Salam, Safnas F; Liu, Jing; Gray, George; Sterling, Alyssa D; Wunderlich, Mark; Landero-Figueroa, Julio; Garrett, Joan T; Merino, Edward J
Published In ChemMedChem, (2019 11 20)
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.
PubMed ID: 31696673
MeSH Terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/chemistry; Antineoplastic Agents/pharmacology*; Cell Line; Cell Proliferation/drug effects; Cell Survival/drug effects; Cyclization; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Microsomes, Liver/chemistry; Microsomes, Liver/metabolism; Molecular Structure; Oxidation-Reduction; Phosphatidylinositol 3-Kinases/metabolism*; Protein Kinase Inhibitors/chemical synthesis; Protein Kinase Inhibitors/chemistry; Protein Kinase Inhibitors/pharmacology*; Reactive Oxygen Species/analysis; Reactive Oxygen Species/metabolism; Structure-Activity Relationship