title: Synthesis and biological evaluation of novel 2-phenylquinazoline-4-amine derivatives: identification of 6-phenyl-8H-benzo[g]quinazolino[4,3-b]quinazolin-8-one as a highly potent inducer of NAD(P)H quinone oxidoreductase 1.
abstract: A novel series of quinazoline compounds (2-14) incorporating biologically active heterocyclic moieties were designed and synthesized. The structure of the newly synthesized compounds was recognized on the basis of elemental analyses, IR,1H-NMR,13C-NMR and mass spectral data. All compounds were evaluated for their ability to induce the cytoprotective enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) using a quantitative bioassay and a docking study was performed in the Kelch domain of Keap1 obtained from the Protein Data Bank (PDB ID: 4IQK) to explore the ability of the synthesized compounds to block the Nrf2-binding site of Keap1. All of the synthesized compounds showed concentration-dependent inducer activity with potencies in the low- or sub-micromolar range. Compound 12 was the most potent inducer in this new series, with a concentration that doubles the specific activity of NQO1 (CD value) of 70 nM. The identification of this compound offers a new chemical scaffold for future development of highly potent inducers.
authors.affiliation: a Department of Pharmacognosy , College of Pharmacy, King Saud University , Riyadh , Kingdom of Saudi Arabia.|b Drug Radiation Research Department , National Center for Radiation Research & Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA) , Nasr City , Cairo , Egypt.
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Ghorab
authors.affiliation: a Department of Pharmacognosy , College of Pharmacy, King Saud University , Riyadh , Kingdom of Saudi Arabia.
authors.forename: Mansour S
authors.initials: MS
authors.lastname: Alsaid
authors.affiliation: b Drug Radiation Research Department , National Center for Radiation Research & Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA) , Nasr City , Cairo , Egypt.
authors.forename: Marwa G
authors.initials: MG
authors.lastname: El-Gazzar
authors.affiliation: c Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee , Dundee , UK.
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.affiliation: c Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee , Dundee , UK.|d Departments of Medicine and Pharmacology and Molecular Sciences , Johns Hopkins University School of Medicine , Baltimore , MD , USA , and.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: a Department of Pharmacognosy , College of Pharmacy, King Saud University , Riyadh , Kingdom of Saudi Arabia.|e Phytochemistry Department , National Research Centre , Dokki , Giza , Egypt.
authors.forename: Abdelaaty A
authors.initials: AA
authors.lastname: Shahat
mesh_terms: D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000614175:2-phenylquinazoline-4-amine; C000614176:6-phenyl-8H-benzo(g)quinazolino(4,3-b)quinazolin-8-one; D011799:Quinazolines; D052999:Quinazolinones; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: NAD(P)H; quinazoline; synthesis