Mitoflaxone, also known as flavone acetic acid is a synthetic flavonoid that has been studied as an antitumor agent. Mitoflaxone was involved in phase II clinical trials in Europe for patients with advanced colorectal carcinoma and for patients with advanced malignant melanoma. Despite the promising preclinical activity, this drug didn’t demonstrate any clinical activity. Further studies of the drug were suspended.

Vatiquinone is the international non-proprietary name for Edison Pharmaceuticals’ EPI-743, an orally bioavailable small molecule being developed by the company for inherited mitochondrial diseases. EPI-743 is a member of the para-benzoquinone class of drugs. The mechanism of action of EPI-743 involves augmenting the synthesis of glutathione, optimizing metabolic control, enhancing the expression of genetic elements critical for cellular management of oxidative stress, and acting at the mitochondria to regulate electron transport. EPI-743 is a compound being developed by BioElectron (previously known as Edison Pharmaceuticals) to treat Friedreich’s ataxia (FA), a rare, autosomal recessive genetic disorder. The regulation of oxidative stress is disturbed in people with FA. EPI-743 targets NADPH quinone oxidoreductase 1 (NQO1), helping to increase the biosynthesis of glutathione, a compound essential for the control of oxidative stress. The drug does not target any FA-specific biochemical pathways directly, but helps to improve the regulation of cellular energy metabolism in general. Vatiquinone has been investigated for the treatment and prevention of retinopathy, rett syndrome, parkinson's disease, noise-induced hearing loss, and methylmalonic aciduria and homocystinuria, Cblc type. The FDA previously granted orphan drug designation for Edison’s EPI-743 to treat inherited respiratory chain diseases of the mitochondria and Friedreich’s ataxia. The company received orphan drug designation for EPI-743 from the Japanese Ministry of Health, Labour and Welfare and European Medicines Agency Committee on Orphan Products for the treatment of Leigh syndrome.

Tocofenoxate is a semisynthetic tocopherol derivative. Vitamin E supplement.

Vadimezan (5,6-dimethyl(xanthenone-4-acetic acid), ASA404, DMXAA) is a fused tricyclic analogue of flavone acetic acid with potential antineoplastic activity. In pre-clinical mouse tumour models it was demonstrated that administration of Vadimezan rapidly leads to disruption of the existing vasculature in the tumour and consequent haemorrhagic necrosis of the tumour. This was consistent with the finding that a single dose of Vadimezan induced a prolonged reduction in the growth of xenografted tumours in animal models. The ability to disrupt the vasculature in these pre-clinical models has been attributed to a rapid induction of cytokines, particularly TNFα (tumour necrosis factor α), serotonin and nitric oxide, resulting in hemorrhagic necrosis and a decrease in angiogenesis. Despite the fact that the molecular targets for the drug remained unknown, the promising pre-clinical results led to Vadimezan being selected for clinical development. Results of Phase I trials showed some restriction of tumour blood flow within 24 h of treatment, although this was not as dramatic as seen in pre-clinical models. Unlike the animal models, there was also very little evidence for the rapid death of blood vessels or for increases in TNFα levels in human tumors. No difference in antitumour activity, cytokine induction or toxicity was observed between two parallel Phase I trials, one dosed weekly and the other dosed every 3 weeks. Therefore the drug proceeded to Phase II clinical trials, dosed every 21 days in combination with chemotherapeutic agents. These trials indicated the drug had small benefits in the treatment of non-small-cell lung cancer and prostate cancer. However, a subsequent Phase III clinical trial was not able to reproduce this response and clinical development was halted.

Quercetin is a unique bioflavonoid that has been extensively studied by researchers over the past 30 years. Quercetin, the most abundant of the flavonoids (the name comes from the Latin –quercetum, meaning oak forest, quercus oak) consists of 3 rings and 5 hydroxyl groups. Quercetin is a member of the class of flavonoids called flavonoles and forms the backbone for many other flavonoids including the citrus flavonoids like rutin, hesperidins, Naringenin and tangeritin. It is widely distributed in the plant kingdom in rinds and barks. The best described property of Quercetin is its ability to act as antioxidant. Quercetin seems to be the most powerful flavonoids for protecting the body against reactive oxygen species, produced during the normal oxygen metabolism or are induced by exogenous damage [9, 10]. One of the most important mechanisms and the sequence of events by which free radicals interfere with the cellular functions seem to be the lipid peroxidation leading eventually the cell death. To protect this cellular death to happen from reactive oxygen species, living organisms have developed antioxidant line of defense systems [11]. These include enzymatic and non-enzymatic antioxidants that keep in check ROS/RNS level and repair oxidative cellular damage. The major enzymes, constituting the first line of defence, directly involved in the neutralization of ROS/RNS are: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) The second line of defence is represented by radical scavenging antioxidants such as vitamin C, vitamin A and plant phytochemicals including quercetin that inhibit the oxidation chain initiation and prevent chain propagation. This may also include the termination of a chain by the reaction of two radicals. The repair and de novo enzymes act as the third line of defence by repairing damage and reconstituting membranes. These include lipases, proteases, DNA repair enzymes and transferases. Quercetin is a specific quinone reductase 2 (QR2) inhibitor, an enzyme (along with the human QR1 homolog) which catalyzes metabolism of toxic quinolines. Inhibition of QR2 in plasmodium may potentially cause lethal oxidative stress. The inhibition of antioxidant activity in plasmodium may contribute to killing the malaria causing parasites.

Diosmin is a flavone indicated for the treatment of venous disease i.e., chronic venous insufficiency (CVI) including spider and varicose veins, leg swelling (edema), stasis dermatitis and venous ulcers. Diosmin is also used as a stand-alone or surgical adjunctive therapy in hemorrhoidal disease. There are extensive clinical trials that show diosmin improves all stages of venous disease including venous ulcers and improves quality of life. Diosmin prolongs the vasoconstrictor effect of norepinephrine on the vein wall, increasing venous tone, and therefore reducing venous capacitance, distensibility, and stasis. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI. Diosmin improves lymphatic drainage by increasing the frequency and intensity of lymphatic contractions, and by increasing the total number of functional lymphatic capillaries. Furthermore, diosmin with hesperidine decreases the diameter of lymphatic capillaries and the intralymphatic pressure. Diosmin reduces the expression of endothelial adhesion molecules (ICAM1, VCAM1), and inhibits the adhesion, migration, and activation of leukocytes at the capillary level. This leads to a reduction in the release of inflammatory mediators, principally oxygen free radicals, and prostaglandins (PGE2, PGF2a). Diosmin is currently a prescription medication in some European countries (under the Dio-PP, Venotec, Daflon etc. tradenames), and is sold as a nutritional supplement in the United States.

Vitamin E quinone Alpha-tocopherylquinone is formed during free radical attack on vitamin E and has been shown to undergo reduction by NQO1 (NAD(P)H dehydrogenase [quinone] 1) to generate vitamin E hydroquinone. Since it has been recognized that alpha-tocopherylquinone in living tissue for global assessment of antioxidative defense system. The ratio of alpha-tocopherol alpha-tocopherylquinone concentrations were increased under oxidative stress with the exception of plasma. Alpha-tocopherylquinone and a low fat diet have positive effect on a patient with chronic continuous ulcerative colitis. The patient's condition improved dramatically with both colonic and extraintestinal manifestations of the disease. Withdrawal of alpha-tocopherylquinone for periods of one to two days produced recurrence of inflammation, which was again reduced upon re-introduction of alpha-tocopherylquinone.

Glabridin is an isoflavane found in the root extract of licorice (Glycyrrhiza glabra). Glabridin is considered to be a phytoestrogen and has been associated with numerous biological properties ranging from antioxidant, anti-inflammatory, neuroprotective, anti-atherogenic effects, to the regulation of energy metabolism, but also including anti-tumorigenic, anti-nephritic, antibacterial and skin-whitening activities. A glabridin-enriched extract is widely used in a cosmetic formulation as anti-inflammatory, antioxidant and skin whitening agent. Anti-inflammatory action of glabridin is linked to downregulation of NF-κB, AP-1 and MAPKS signaling. Glabridin-induced attenuation of atherosclerosis is related to a reduction in macrophages-associated oxidation of low-density lipoprotein.

Hesperidin is a flavanone glycoside found in citrus fruits. Its aglycone form is called hesperetin. Its name is derived from the word "hesperidium", for fruit produced by citrus trees. Hesperidin was first isolated in 1828 by French chemist Lebreton from the white inner layer of citrus peels (mesocarp, albedo). As a flavanone found in citrus fruits (such as oranges, lemons or pummelo fruits), hesperidin is under laboratory research for possible biological properties. One area of research is focused on the possible chemopreventive effects of hesperidin, but there is no current proof that hesperidin has this role in human cancer mechanisms. Hesperidin was effective in an animal model of Alzheimer's, alleviating pathological changes induced by aluminum. Early research suggests that taking one tablet of a specific product (Daflon 500, Les Laboratoires Servier) containing hesperidin and diosmin by mouth for 45 days decreases blood sugar levels and improves blood sugarcontrol in women with type 2 diabetes. For Rheumatoid arthritis (RA): early research suggests that drinking a beverage containing alpha-glucosyl hesperidin for 12 weeks improves symptoms of RA. Orally, hesperidin can cause gastrointestinal side effects, including abdominal pain, diarrhea, and gastritis. Headache can also occur in some patients. The possible anti-inflammatory action of hesperidin is probably due to the possible anti-inflammatory action of its aglycone hesperetin. Hesperetin appears to interfere with the metabolism of arachidonic acid as well as with histamine release. Hesperetin appears to inhibit phospholipase A2, lipoxygenase and cyclo-oxygenase. There is evidence that hesperetin inhibits histamine release from mast cells, which would account for the possible anti-allergic activity of hesperidin. The possible hypolipidemic effect of hesperidin is probably due to hesperetin's possible action in lipid lowering. Hesperetin may reduce plasma cholesterol levels by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, as well as acyl coenzyme A: cholesterol acytransferase (ACAT). Inhibition of these enzymes by hesperetin has been demonstrated in rats fed a high cholesterol diet. The mechanism of hesperidin's possible vasoprotective action is unclear. Animal studies have shown that hesperidin decreases microvascular permeability. Hesperidin, itself or via hesperetin, may protect endothelial cells from hypoxia by stimulating certain mitochondrial enzymes, such as succinate dehydrogenase. The mechanism of hesperidin's possible anticarcinogenic action is also unclear. One explanation may be the inhibition of polyamine synthesis. Inhibition of lipoxygenase and cyclo-oxygenase is another possibility.