Ghorab Mostafa M, Alsaid Mansour S, El-Gazzar Marwa G, Higgins Maureen, Dinkova-Kostova Albena T, Shahat Abdelaaty A
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.
J Enzyme Inhib Med Chem. 2016;31(sup1):34-39. doi: 10.3109/14756366.2016.1163343. Epub 2016 Apr 1.
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, H-NMR, 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.
设计并合成了一系列包含生物活性杂环部分的新型喹唑啉化合物（2 - 14）。根据元素分析、红外光谱、氢核磁共振、碳核磁共振和质谱数据确定了新合成化合物的结构。使用定量生物测定法评估了所有化合物诱导细胞保护酶NAD(P)H：醌氧化还原酶1（NQO1）的能力，并对从蛋白质数据库（PDB ID：4IQK）获得的Keap1的Kelch结构域进行了对接研究，以探索合成化合物阻断Keap1的Nrf2结合位点的能力。所有合成化合物均表现出浓度依赖性诱导活性，效力在低或亚微摩尔范围内。化合物12是该新系列中最有效的诱导剂，其使NQO1比活性加倍的浓度（CD值）为70 nM。该化合物的鉴定为未来开发高效诱导剂提供了一种新的化学骨架。
