8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications

Figures & data

Figure 1 Structure of 8-hydroxyquinoline.

Figure 2 8-Hydroxyquinoline derivatives with potent antineurodegenerative activity.

Abbreviations: HLA-20, 5-((4-(prop-2-ynyl)piperazin-1-yl)methyl)quinolin-8-ol; M30, 5-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol; VK-28, 5-((4-(2-hydroxyethyl) piperazin-1-yl)methyl)quinolin-8-ol.

Figure 3 Clioquinol and its electron donor sites (A) and 5,7-diiodo-8-hydroxyquinoline (B).

Figure 4 M30 and HLA-20 are hybrids of Ladostigil and VK-28.

Abbreviations: HLA-20, 5-((4-(prop-2-ynyl)piperazin-1-yl)methyl)quinolin-8-ol; M30, 5-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol; VK-28, 5-((4-(2-hydroxyethyl) piperazin-1-yl)methyl)quinolin-8-ol.

Figure 5 Propargylamine moiety.

Figure 6 Metabolism of dopamine and actions of 8-hydroxyquinoline derivatives.

Abbreviations: HLA-20, 5-((4-(prop-2-ynyl)piperazin-1-yl)methyl)quinolin-8-ol; M30, 5-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol; VK-28, 5-((4-(2-hydroxyethyl) piperazin-1-yl)methyl)quinolin-8-ol; MAO, monoamine oxidase enzyme; OḢ, reactive hydroxyl radical.

Figure 7 Structure of 8-hydroxyquinoline-uracil metal complexes.

Figure 8 Chemical structures of nitroxoline (NQ) and clioquinol (CQ).

Figure 9 Glucoconjugates of 8-hydroxyquinoline and clioquinol.

Abbreviations: Glu8HQ, glucoconjugate of 8-hydroxyquinoline; GluCQ, glucoconjugate of clioquinol.

Figure 10 Chemical structures of HQMABS and metal complexes.

Abbreviation: HQMABS, 4-benzenesulfonamide.

Figure 11 Quaternary ammonium salts of 8-hydroxyquinoline.

Figure 12 Structure of AMD3100.

Figure 13 Chemical structures of hydroxyquinoline-polyamine conjugates using hydroxyquinoline conjugation with polyamine backbone or polyazamacrocycles.

Figure 14 Substituted 8-hydroxyquinoline derivatives.

Figure 15 Structure of NSC3852.

Abbreviation: NSC3852, 5-nitroso-8-hydroxyquinoline.

Figure 16 8-Hydroxyquinoline is used as a building block for artificial carbohydrate receptors.

Figure 17 FOXO1 functions are related to glucose homeostasis and providing protection against oxidative stress.

Abbreviations: FOXO1, forkhead box protein O1; SOD, superoxide dismutase.

Figure 18 The role of CQ as Zn ionophore in controlling blood glucose level via inhibition of FOXO1.

Abbreviations: IIS, Insulin/insulin-like growth factor-1 signaling pathway; CQ, clioquinol; FOXO1, forkhead box protein O1; G6Pase, glucose-6-phosphatase; SOD, superoxide dismutase; PEPCK, phosphoenolpyruvate carboxykinase; Pi, phosphorylation.

Figure 19 8HQ derivatives with different substitutions.

Abbreviations: CQ, clioquinol; HQ, hydroxyquinoline.

Figure 20 Liver functions on controlling glucose metabolism and antidiabetic actions of 8-hydroxyquinoline derivatives.

Abbreviations: CQ, clioquinol; FOXO1, forkhead box protein O1; G6Pase, glucose-6-phosphatase; GLUT-1, glucose transporter; HIF-1α, hypoxia inducible factor; HLA-20, 5-((4-(prop-2-ynyl)piperazin-1-yl)methyl)quinolin-8-ol; InsR, insulin receptor; M30, 5-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol; PEPCK, phosphoenolpyruvate carboxykinase.

Table 1 Brief review of 8-hydroxyquinoline (8HQ) and its derivatives

8HQ is a lipophilic compound with diverse bioactivities which are exerted via its chelating ability.

Ionophore is a subset of metal-binding compounds which are capable of transferring multiple metal ions across biological membranes, either in or out of cells.

Antineurodegenerative activity

• 8HQ derivatives are small lipophilic compounds that are capable of entering the blood–brain barrier into the target site in the brain.

• As selective chelator to certain types of metal ions, 8HQ derivatives decrease neurotoxicity caused by metal-protein interaction.

• As antioxidant, 8HQ derivatives reduce ROS formation and oxidative damage to the brain.

Anticancer activity

• Fe is a redox-reactive metal ion that generates ROS and serves as nutrient for cancer cell growth.

• 8HQ is capable of forming complexes with metal that incorporated in enzymes required for DNA synthesis. This results in an antiproliferative effect of the compound.

• 8HQ-Fe lipophilic complex intercalates with DNA strands and causes massive DNA damage leading to cancer cell apoptosis.

• Cu is a cofactor for tumor angiogenesis and is found in relatively high levels in tissue and serum of cancer patients compared to normal subjects. This indicates the potential of using Cu as a selective target for cancer treatment.

• CQ acts as Cu ionophore to transport Cu into cells where it exerts activity. CQ-Cu complex interacts with electron donor groups located outside of proteasome leading to proteasome inhibition and apoptosis.

Antimicrobial activity

• 8HQ derivatives were reported to exert antimicrobial activities against a variety of microorganisms such as Mycobacterium tuberculosis, Escherichia coli, Staphylococcus aureus (including MRSA), Streptococcus mutans, Candida albicans, HIV, Plasmodium falciparum and Toxoplasma gondii.

Antioxidant activity

• 8HQ and its derivatives are potent antioxidants.

• 8HQ metal complexes were reported with improved antioxidant activity (SOD assay) compared to free ligand 8HQ.

Anti-inflammatory activity

• 8HQ inhibits nitric oxide production at transcriptional level via inhibition of NF-κB and C/EBPβ DNA binding.

Transportation of Pb across red blood cells (RBC)

• Long-term exposure to Pb-containing environment causes lead poisoning. Excessive Pb ions are sequestered in RBC and affect Zn-containing RBC enzyme leading to cardiovascular risk.

• Most of the clinically used Pb chelators are not capable of passing across erythrocyte membrane thereby giving only a short period of therapeutic benefits.

• CQ acts as Zn ionophore to increase Zn intracellular level of RBC.(br/)Additional Zn ion is believed to displace Pb from enzyme and promote Pb escape into the extracellular space, where it is effectively chelated by Pb chelators.

• CQ and other classes of Zn ionophore are considered to be promising compounds that should be further developed as combined agents with Pb chelators to improve treatment outcome.

Building block for artificial carbohydrate receptors

• 8HQ-based receptors exhibit high affinity to β-galactoside thereby indicating their potential as artificial carbohydrate receptors.

Potential antidiabetic activity

• FOXO proteins are crucial regulators against oxidative stress conditions.

• Nuclear FOXO1 is important for the expression of many downstream effector genes, which function to maintain glucose homeostasis and protect against oxidative stress condition.

• FOXO1 exclusion from the nucleus activates β-cell proliferation and insulin production; however, this also reduces oxidative stress resistance leading to β-cell apoptosis.

• A compound is considered diabetogenic if it has the ability to harm β-cells, including decreasing antioxidant defenses and activating β-cell proliferation leading to β-cell apoptosis.

• 8HQ has been reported as a diabetogenic agent due to its ability to induce Zn-dependent FOXO1 phosphorylation via action of the Zn ionophore as well as its acidity caused by release of H^+ from OH groups. These phenomena lead to β-cell apoptosis, which affects insulin production and control of blood glucose.

• It was suggested that the ideal antidiabetic agent should be capable of decreasing blood glucose level via induction of FOXO1 phosphorylation as well as minimizing β-cell damage.

• CQ is considered a potential antidiabetic agent. It has the ability to induce FOXO1 phosphorylation without diabetogenic effect. It was suggested that increased lipophilic, electronic, and steric effects may be involved in the lack of diabetogenicity.

• 8HQ-based antineurodegenerative agents such as M30 and HLA-20 have beneficial effects on controlling blood glucose via Fe chelation.(br/)Glucose metabolism is directly controlled by hepatic factors. The decreased hepatic Fe levels can mimic hypoxic conditions that results in lower blood glucose level.

Abbreviations: C/EBPβ, CCAAT/enhancer-binding protein beta; CQ, clioquinol; HIV, Human immunodeficiency virus; MRSA, methicillin-resistant Staphylococcus aureus; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ROS, reactive oxygen species; SOD, superoxide dismutase; HQ, hydroxyquinoline; FOXO, forkhead box protein.

Table 2 Bioactivities and specific mechanisms of 8-hydroxyquinoline (8HQ) and its derivatives

Action	Activity	Mechanism
Cu chelator	Antineurodegenerative	Reduces neurotoxicity caused by metal–protein interaction
	Anticancer	Inhibits tumor growth and metastasis by antiangiogenesis
		Induces apoptosis by inactivation of SOD1 enzyme
	Antimicrobial and antiparasitic	Inhibits microbial enzymes
	Antioxidant	Mimics SOD activity
Fe chelator	Antineurodegenerative	Reduces neurotoxicity caused by metal–protein interaction
	Anticancer	Inhibits tumor growth by antiproliferation
		Inhibits enzymes required for DNA synthesis
		Induces apoptosis by DNA intercalation of 8HQ-Fe complex
	Antimicrobial and antiparasitic	Inhibits microbial enzymes
	Antidiabetic	Alters glucose metabolism via expression of hepatic factors
Zn chelator	Antineurodegenerative	Allows degradation of misfolded proteins
		Reduces neurotoxicity caused by metal–protein interaction
Cu ionophore	Antineurodegenerative	Restores brain metal homeostasis by redistribution of intracellular
		Cu ions and delivery of Cu ions to the brain areas where they are depleted
		Activates protective signaling cascades
	Anticancer	Inhibits apoptosis via proteasome inhibition
Zn ionophore	Antineurodegenerative	Restores brain metal homeostasis by redistribution of intracellular
		Zn ions and delivery of Zn ions to brain areas where they are depleted
	Anticancer	Induces apoptosis via lysosomal disruption and NF-κB inactivation
	Antidiabetic	Increases insulin production and inhibits hepatic enzymes required for gluconeogenesis via induction of Zn-dependent FOXO1 phosphorylation
	Pb poisoning treatment	Improves effect of Pb chelators by promoting Pb escape from red blood cells into extracellular space

Abbreviations: NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; SOD, superoxide dismutase; FOXO, forkhead box protein.