Novel quinazolin-4-one derivatives as potentiating agents of doxorubicin cytotoxicity

Monika Pospisilova; Martin Andrs; Martina Seifrtova; Radim Havelek; Daniel Jun; Pavel Tomsik; Lukas Prchal; Rafael Dolezal; Ales Tichy; Tomas Kucera; Jan Korabecny; Martina Rezacova

doi:10.1016/j.bioorg.2018.10.001

Novel quinazolin-4-one derivatives as potentiating agents of doxorubicin cytotoxicity

Bioorg Chem. 2019 Feb:82:204-210. doi: 10.1016/j.bioorg.2018.10.001. Epub 2018 Oct 6.

Authors

Affiliations

¹ Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova 870, 500 03 Hradec Kralove, Czech Republic.
² Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 81, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
³ Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 81, 500 05 Hradec Kralove, Czech Republic.
⁴ Department of Radiobiology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
⁵ Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
⁶ Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 81, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Electronic address: [email protected].
⁷ Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova 870, 500 03 Hradec Kralove, Czech Republic. Electronic address: [email protected].

PMID: 30326402
DOI: 10.1016/j.bioorg.2018.10.001

Abstract

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.

Keywords: Cancer; Chemosensitization; DNA-dependent protein kinase; NU7441; Phosphatidylinositol 3-kinase; Poly(ADP-ribose) polymerase-1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Outbred Strains
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
DNA-Activated Protein Kinase / antagonists & inhibitors
Doxorubicin / pharmacology*
Drug Design
Drug Synergism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Enzyme Inhibitors / toxicity
Female
HT29 Cells
Humans
Mice
Morpholines / chemical synthesis
Morpholines / pharmacology*
Morpholines / toxicity
Nuclear Proteins / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Quinazolinones / chemical synthesis
Quinazolinones / pharmacology*
Quinazolinones / toxicity

Substances

Antineoplastic Agents
Enzyme Inhibitors
Morpholines
Nuclear Proteins
Quinazolinones
Doxorubicin
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
DNA-Activated Protein Kinase
PRKDC protein, human