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

• Published in: European journal of medicinal chemistry Vol. 212; pp. 113153 - 113167
• Main Authors: Zhang, Yuxia, Yang, Jiaxin, Meng, Tingting, Qin, Yajuan, Li, Tingyou, Fu, Junjie, Yin, Jian
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2021; Elsevier
• Subjects: 8-Hydroxyquinoline; Animals; Anticancer agent; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Proliferation - drug effects; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Male; Membrane Potential, Mitochondrial - drug effects; Metal chelator; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Nitric Oxide - metabolism; Nitric oxide donor; Oxyquinoline - chemical synthesis; Oxyquinoline - chemistry; Oxyquinoline - pharmacology; Pharmacology & Pharmacy; Reactive Oxygen Species - metabolism; ROS-Responsive prodrug; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; 8-Hydroxyquinoline; ROS-Responsive prodrug; Nitric oxide donor; Anticancer agent; Metal chelator
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113153

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. [Display omitted] •HQ-NO-11 is a nitric oxide (NO)-releasing 8-hydroxyquinonline (8-HQ) derivative.•HQ-NO-11 is a prochelator that is activated by ROS to generate the 8-HQ scaffold.•HQ-NO-11 shows potent and selective cytotoxicity toward cancer cells in vitro.•HQ-NO-11 inhibits tumor growth in vivo more effectively than 8-HQ.•Both NO release and metal binding are essential for the cytotoxicity of HQ-NO-11.