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

TY - JOUR

T1 - Synthesis and biological evaluation of novel 2-phenylquinazoline-4-amine derivatives

T2 - 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

AU - Ghorab, Mostafa M.

AU - Alsaid, Mansour S.

AU - El-Gazzar, Marwa G.

AU - Higgins, Maureen

AU - Dinkova-Kostova, Albena T.

AU - Shahat, Abdelaaty A.

PY - 2016

Y1 - 2016

N2 - 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, (1)H-NMR, (13)C-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.

AB - 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, (1)H-NMR, (13)C-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.

KW - Synthesis

KW - quinazoline

KW - NAD(P)H

U2 - 10.3109/14756366.2016.1163343

DO - 10.3109/14756366.2016.1163343

M3 - Article

C2 - 27033734

SN - 1475-6366

VL - 31

SP - 34

EP - 49

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

IS - Suppl. 1

ER -