8-Hydroxyquinoline Sulfate: Metal Chelator with Diverse Biological and Industrial Applications

8-Hydroxyquinoline sulfate is a metal chelating agent extracted from coal tar. It has been used in a wide variety of products, from “bag balm” for cows to cosmetics and drugs, for its ability to inhibit the growth of imidazolidinylurea microbes. An ointment formulation containing the sulfate salt of 8-hydroxyquinoline in a petrolatum and lanolin base with skin-protecting activity. Upon topical application, 8-hydroxyquinoline sulfate exhibits antiseptic activity while lanolin moisturizes and softens skin.

Recent Advances in the Synthesis and Biological Activity of 8-Hydroxyquinolines

8-Hydroxyquinoline derivatives are an important group of compounds with rich and diverse biological activities. These compounds incorporate the 8-Hydroxyquinoline sulfate (8-HQ) moiety, which is a bicyclic compound that consists of a pyridine ring fused to phenol, in which the hydroxyl group is attached to position 8. In this respect, the pyridine ring maintains its properties as an electron-deficient entity with a basic nitrogen. The close proximity of the hydroxyl group to the heterocyclic nitrogen makes 8-Hydroxyquinoline sulfate good monoprotic bidentate chelating agents, which form four- and six-covalent complexes with a wide range of metal ions, including Cu2+, Zn2+, Bi2+, Mn2+, Mg2+, Cd2+, Ni2+, Fe3+, and Al3+. 8-Hydroxyquinoline has attracted the attention of chemists, medicinal chemists, and people in health sciences due to its unique physical and chemical properties. The interest in this compound and its derivatives has increased considerably in the last two decades. 8-Hydroxyquinoline sulfate and many of its derivatives have a wide range of pharmacological applications, e.g., as iron-chelators for neuroprotection, as anticancer agents, as inhibitors of 2OG-dependent enzymes, as chelators of metalloproteins.[1]

The rest of the 8-hydroxyquinoline derivatives exhibited weak activity. The results also showed that umbelliferone derivatives with a spacer of 4 carbon atoms exhibit better antifungal activity than those with a spacer of 2 carbon atoms. The chain length may contribute to the activity by influencing the flexibility of the molecules. In addition, the position of the OH group affects the antifungal activity; derivatives with OH at position 8 were more active than those with OH at position 4. In the search for potent BuChE and AChE inhibitors, Hirbod et al. (2017) designed and prepared eight novel compounds incorporating coumarin and 8-Hydroxyquinoline sulfate moieties. These researchers used various dibromoalkanes (n = 3–5) as cross-linkers between 8-Hydroxyquinoline sulfate and coumarin rings in the presence of an aprotic solvent (N,N-dimethylformamide). In addition, the activity levels of these prepared compounds were evaluated against BuChE and AChE using Ellman's method.

8-Hydroxyquinolines: metal chelating properties and medicinal applications

8-Hydroxyquinoline sulfate (8HQ), a quinoline derivative originating in plants as well as from synthesis, has been used as a fungicide in agriculture and a preservative in the textile, wood, and paper industries. 8HQ possesses potent coordinating ability and good metal recognition properties, which means it is widely used for analytical and separation purposes as well as for metal chelation. Many diseases arise from the loss of homeostasis including metal overload and deficiency, which are caused by abnormal metal metabolism or metal absorption. Of all the hydroxyquinoline derivatives, 8-Hydroxyquinoline sulfate is the most interesting one to be explored, owing to its multifunctional properties, such as diverse bioactivities and therapeutic potentials. 8HQ is the only one, among seven isomeric monohydroxyquinolines, capable of forming complexes with divalent metal ions through chelation. Most bioactivities of 8HQ and its derivatives originate from their chelating ability. As previously mentioned, metal imbalance is the leading cause for many diseases, therefore, 8-Hydroxyquinoline sulfate is a potent chelator that may restore metal balance and be useful for the treatment of metal-related diseases.[2]

The formed Fe-8HQ lipophilic complex is capable of entering and being distributed within cells, causing massive breakage of DNA strands. In order to repair damaged DNA, large quantities of adenosine triphosphate are required, which consequently leads to cellular adenosine triphosphate depletion and finally cell death. As such, possible mechanisms of DNA damage were proposed. In other words, the Fe-8HQ complex acts as a cytostatic drug. Another possible mechanism is that the Fe-chelator complex induces membrane damage, that leads to loss of calcium homeostasis, which triggers endonuclease to cleave DNA in an apoptotic-like manner. It has been further demonstrated that nitro containing 8-Hydroxyquinoline sulfate derivatives such as nitroxoline (8-hydroxy-5-nitroquinoline; NQ) exerted more potent anticancer activity, with a IC50 of 5–10-fold less than that of CQ (halogenated 8HQ derivative), and may be less neurotoxic. Metal imbalance plays a crucial role in the etiology of many diseases that affect quality of life. The objectives of treatment are not only aimed at restoring metal balance but also at minimizing cellular damage. 8-Hydroxyquinoline sulfate and its derivatives possess diverse pharmacological and biological activities, which are a result of their chelating ability.

Anticalculus and antiplaque activity of 8-hydroxyquinoline sulfate

The effect of 8-hydroxyquinoline sulfate on the formation of artificial calculi, rat calculus, and dog plaque plus its ability to remove dog plaque were studied. Several chemically related agents were also evaluated for their anticalculus effects. The most effective anticalculus agent was 8-hydroxyquinoline sulfate. At concentrations of 4 or 5%, swabbed over molar teeth, it was essentially equally effective in retarding the formation of rat calculus.  Visual evaluation of oral tissues in the swabbing tests plus visual and histopathological evaluation of oral tissues in the mouthrinse procedure showed it had no irritating or toxic effects. In dogs, the teeth treated with 4% 8-hydroxyquinoline sulfate nine times during a five-day period had 93.7 to 98.4% less buccal plaque than vehicle-treated teeth. The antiplaque effect was considerable in both canines and fourth premolars. In older dogs, teeth treated with 4% 8-hydroxyquinoline sulfate 15 times during a ten-day period had 33 to 46.1% less plaque than when treated with the vehicle.[3]

References

[1]Saadeh HA, Sweidan KA, Mubarak MS. Recent Advances in the Synthesis and Biological Activity of 8-Hydroxyquinolines. Molecules. 2020 Sep 21;25(18):4321. doi: 10.3390/molecules25184321. Erratum in: Molecules. 2022 Jul 05;27(13):4306. doi: 10.3390/molecules27134306. PMID: 32967141; PMCID: PMC7571046.

[2]Prachayasittikul V, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. 8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications. Drug Des Devel Ther. 2013 Oct 4;7:1157-78. doi: 10.2147/DDDT.S49763. PMID: 24115839; PMCID: PMC3793592.

[3]Depalma, P D et al. “Anticalculus and antiplaque activity of 8-hydroxyquinoline sulfate.” Journal of dental research vol. 55,2 (1976): 292-8. doi:10.1177/00220345760550022301