Novel quinazolin-4-one derivatives as potentiating agents of doxorubicin cytotoxicity
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
30326402
DOI
10.1016/j.bioorg.2018.10.001
PII: S0045-2068(18)30806-X
Knihovny.cz E-resources
- Keywords
- Cancer, Chemosensitization, DNA-dependent protein kinase, NU7441, Phosphatidylinositol 3-kinase, Poly(ADP-ribose) polymerase-1,
- MeSH
- Apoptosis drug effects MeSH
- HT29 Cells MeSH
- Quinazolinones chemical synthesis pharmacology toxicity MeSH
- Doxorubicin pharmacology MeSH
- Enzyme Inhibitors chemical synthesis pharmacology toxicity MeSH
- Nuclear Proteins antagonists & inhibitors MeSH
- Humans MeSH
- Morpholines chemical synthesis pharmacology toxicity MeSH
- Mice MeSH
- Animals, Outbred Strains MeSH
- Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors MeSH
- Cell Proliferation drug effects MeSH
- DNA-Activated Protein Kinase antagonists & inhibitors MeSH
- Antineoplastic Agents pharmacology MeSH
- Drug Design MeSH
- Drug Synergism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Quinazolinones MeSH
- Doxorubicin MeSH
- Enzyme Inhibitors MeSH
- Nuclear Proteins MeSH
- Morpholines MeSH
- PARP1 protein, human MeSH Browser
- Poly (ADP-Ribose) Polymerase-1 MeSH
- PRKDC protein, human MeSH Browser
- DNA-Activated Protein Kinase MeSH
- Antineoplastic Agents MeSH
We report the design, synthesis and biological evaluation of 17 novel 8-aryl-2-morpholino-3,4-dihydroquinazoline derivatives based on the standard model of DNA-PK and PI3K inhibitors. Novel compounds are sub-divided into two series where the second series of five derivatives was designed to have a better solubility profile over the first one. A combination of in vitro and in silico techniques suggested a plausible synergistic effect with doxorubicin of the most potent compound 14d on cell proliferation via DNA-PK and poly(ADP-ribose) polymerase-1 (PARP-1) inhibition, while alone having a negligible effect on cell proliferation.
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