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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-6 |
| Number of pages | 6 |
| Journal | Journal of Enzyme Inhibition and Medicinal Chemistry |
| DOIs | |
| State | Accepted/In press - Mar 23 2016 |
Fingerprint
Keywords
- NAD(P)H
- quinazoline
- synthesis
ASJC Scopus subject areas
- Drug Discovery
- Pharmacology
Cite this
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. / Ghorab, Mostafa M.; Alsaid, Mansour S.; El-Gazzar, Marwa G.; Higgins, Maureen; Dinkova-Kostova, Albena T.; Shahat, Abdelaaty A.
In: Journal of Enzyme Inhibition and Medicinal Chemistry, 23.03.2016, p. 1-6.Research output: Contribution to journal › Article
}
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 - 2016/3/23
Y1 - 2016/3/23
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, 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.
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, 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.
KW - NAD(P)H
KW - quinazoline
KW - synthesis
UR - http://www.scopus.com/inward/record.url?scp=84962045448&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962045448&partnerID=8YFLogxK
U2 - 10.3109/14756366.2016.1163343
DO - 10.3109/14756366.2016.1163343
M3 - Article
SP - 1
EP - 6
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
SN - 1475-6366
ER -