2. Academic Validation
  3. Nitric oxide-donating and reactive oxygen species-responsive prochelators based on 8-hydroxyquinoline as anticancer agents

Nitric oxide-donating and reactive oxygen species-responsive prochelators based on 8-hydroxyquinoline as anticancer agents

  • Eur J Med Chem. 2021 Feb 15:212:113153. doi: 10.1016/j.ejmech.2021.113153.
Yuxia Zhang 1,  Jiaxin Yang 2,  Tingting Meng 1,  Yajuan Qin 1,  Tingyou Li 3,  Junjie Fu 4,  Jian Yin 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Nanjing Medical University, Nanjing, 211166, PR China.
  • 2 Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, PR China.
  • 3 School of Pharmacy, Nanjing Medical University, Nanjing, 211166, PR China. Electronic address: l_tingyou@njmu.edu.cn.
  • 4 Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, PR China. Electronic address: jfu@jiangnan.edu.cn.
  • 5 Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, PR China. Electronic address: jianyin@jiangnan.edu.cn.
PMID: 33453603 DOI: 10.1016/j.ejmech.2021.113153
Abstract

Metal ion chelators based on 8-hydroxyquinoline (8-HQ) have been widely explored for the treatment of many diseases. When aimed at being developed into potent Anticancer agent, a largely unmet issue is how to avoid nonspecific chelation of metal ions by 8-HQ in normal cells or tissues. In the current work, a two-step strategy was employed to both enhance the Anticancer activity of 8-HQ and improve its Cancer cell specificity. Considering the well-known Anticancer activity of nitric oxide (NO), NO donor furoxan was first connected to 8-HQ to construct HQ-NO conjugates. These conjugates were screened for their cytotoxicity, metal-binding ability, and NO-releasing efficiency. Selected conjugates were further modified with a ROS-responsive moiety to afford prochelators. Among all the target compounds, prodrug HQ-NO-11 was found to potently inhibit the proliferation of many Cancer cells but not normal cells. The abilities of metal chelation and NO generation by HQ-NO-11 were confirmed by various methods and were demonstrated to be essential for the Anticancer activity of HQ-NO-11. In vivo studies revealed that HQ-NO-11 inhibited the growth of SW1990 xenograft to a larger extent than 8-HQ. Our results showcase a general method for designing novel 8-HQ derivatives and shed light on obtaining more controllable metal chelators.

Keywords

8-Hydroxyquinoline; Anticancer agent; Metal chelator; Nitric oxide donor; ROS-Responsive prodrug.

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