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
  • 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: [email protected].
  • 4. Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, PR China. Electronic address: [email protected].
  • 5. Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, PR China. Electronic address: [email protected].
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.