Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 07, 2019
- Source ID
- 10.1002/cmdc.201900481
Entities
People
- Alyssa D. Sterling
- Edward J Merino
- George Gray
- Haizhou Zhu
- Jing Liu
- Joan T. Garrett
- Julio Landero‐figueroa
- Long Yuan
- Mark Wunderlich
- Rosalin Mishra
- Safnas F. Abdul Salam
Organizations
- Cincinnati Children's Hospital Medical Center
- United States Department of Defense
- University of Cincinnati