Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Bioorganic chemistry, 2019-02, Vol.82, p.204-210

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •17 novel 8-aryl-2-morpholino-3,4-dihydroquinazoline derivatives were developed.•Effective agents in potentiating doxorubicin cytotoxicity.•Synergistic effect via DNA-PK and poly(ADP-ribose) polymerase-1.•Highlighted compound 14d exceeded activity of NU7441.•Potential safety of 14d up-to 30 mg/kg (i.p., mice). 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.