Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City P.O. Box 29, Cairo 11765, Egypt.
Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, UK.
Bioorg Med Chem Lett. 2021 Jun 15;42:128002. doi: 10.1016/j.bmcl.2021.128002. Epub 2021 Mar 31.
Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of fourteen new diiodoquinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail and evaluation of their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The N-(2-chloropyridin-3-yl)-2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio) acetamide 17 was the most potent NQO1 inducer (CD = 25 µM) with free radical scavenging activity (IC = 28 µM) and in vivo median lethal dose (LD) of 500 mg/Kg. The possible radioprotective activity of compound 17 was evaluated in (7 Gy) irradiated mice. Compound 17 showed a reduction in radiation induced oxidative stress as evidenced by the lower levels of ROS, malondialdehyde (MDA) and NQO1 in liver tissues. Moreover, compound 17 showed improvement in the complete blood count (CBC) of irradiated mice and decreased mortality over 30 days following irradiation. Additionally, docking studies inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, confirmed that 17 revealed the same interactions with the key amino acids as those of the co-crystallized ligand. This study identifies 17 as a novel antioxidant that protects against the harmful effect of radiation.
活性氧（ROS）在大多数疾病的发病机制中起着不可或缺的作用。本工作设计并合成了十四种新型二碘喹唑啉酮衍生物，带有苯磺酰胺部分和可变的乙酰胺尾部，并评估了它们通过其经典靶标 NAD(P)H：醌氧化还原酶 1（NQO1）在 Hepa1c1c7 小鼠肝癌细胞中激活核因子红细胞 2 相关因子 2（Nrf2）的能力。N-(2-氯吡啶-3-基)-2-((6,8-二碘-4-氧代-3-(4-磺酰胺基苯基)-3,4-二氢喹唑啉-2-基)硫代)乙酰胺 17 是最有效的 NQO1 诱导剂（CD=25µM），具有自由基清除活性（IC=28µM）和体内半数致死剂量（LD）为 500mg/Kg。在（7Gy）照射的小鼠中评估了化合物 17 的可能放射保护活性。化合物 17 显示出降低辐射诱导的氧化应激的作用，这表现在肝组织中 ROS、丙二醛（MDA）和 NQO1 的水平降低。此外，化合物 17 显示出对受照射小鼠的全血细胞计数（CBC）的改善，并降低了照射后 30 天的死亡率。此外，在 Kelch 样 ECH 相关蛋白 1（Keap1）的 Nrf2 结合位点内进行的对接研究证实，17 与关键氨基酸的相互作用与共结晶配体相同。这项研究确定 17 是一种新型抗氧化剂，可防止辐射的有害影响。
