Design and Synthesis of Novel Coumarin and Naphthalene Derivatives as Nrf2 Modulators

• Main Authors: Ken-Ming Chang, 張耿銘
• Other Authors: Cherng-Chyi Tzeng
• Format: Others
• Language: zh-TW
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/g7n839

博士 === 高雄醫學大學 === 藥學系博士班 === 105 === Recently studies demonstrated that activation of the Nuclear factor erythroid-2-related factor (Nrf2) signaling pathway could reduce the oxidative stress damage and also prevent the normal cell transformation. However, in clinical, over expression of the Nrf2/ARE- regulated detoxification/antioxidation genes has been closely relative to the cancer cells for developing the resistance to chemotherapy and radiotherapy. Therefore, identification of potent Nrf2/ARE signaling activators for chemoprevention as well as Nrf2/ARE signaling inhibitors for overcome tumor cells to develop resistance become very attractive subjects for cancer research. In this dissertation, a series of novel coumarin and naphthalene derivatives have been synthesized. Among them, the coumarin derivative showed higher activity than t-BHQ in the presence of compound 17a, while Naphthalene derivative was the best in compound 34a. It is exciting that these derivatives are not significantly cytotoxicity. Compound 17a has been assay for in vivo and in vitro activity, and it is known that the compound can simultaneously increase mRNA levels of AKR1C1, GCLC and Prx1 in the Nrf2 / ARE pathway. In vivo, it is known that it can increase AKR1C1, GR And HO-1 concentration. Compound 34a was found to be unable to up-regulate the expression of Nrf2 in Western blot analysis, but could induce Nrf2 protein activation in serine 40 phosphorylation. Therefore, this series of novel coumarin and naphthalene derivatives are known to have the ability to scavenge and chemoprevent ROS / RNS and to understand its mechanism of action. In this dissertation, we have developed a strong and novel Nrf2 activator, which can be used as a potential protective agent for disease prevention.