Oxidative Cyclization-Induced Activation of a Phosphoinositide 3-Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics.
Antineoplastic Agents
/ chemical synthesis
Cell Line
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cyclization
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Microsomes, Liver
/ chemistry
Molecular Structure
Oxidation-Reduction
Phosphatidylinositol 3-Kinases
/ metabolism
Protein Kinase Inhibitors
/ chemical synthesis
Reactive Oxygen Species
/ analysis
Structure-Activity Relationship
oxidative cyclization
phosphoinositide 3-kinase inhibitors
prodrugs
reactive oxygen species
synergy effects
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
20 11 2019
20 11 2019
Historique:
received:
19
08
2019
revised:
03
10
2019
pubmed:
7
11
2019
medline:
23
9
2020
entrez:
8
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31696673
doi: 10.1002/cmdc.201900481
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Reactive Oxygen Species
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1933-1939Subventions
Organisme : NIEHS NIH HHS
ID : R15 ES029675
Pays : United States
Organisme : NCI NIH HHS
ID : CA181347
Pays : United States
Organisme : Department of Defense
ID : 1R15ES029675
Pays : International
Organisme : University of Cincinnati Collaborative Advancement Grants Program Strategic Teams to EJM and JTG
Pays : International
Organisme : NSF research experience for undergraduates
ID : 1659648
Pays : International
Organisme : Department of Defense
ID : W81XWH-16-1-0489
Pays : International
Organisme : NSF award
ID : 1828072
Pays : International
Informations de copyright
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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