Figure 7.1:Turmeric Plant
Figure 7.2:Turmeric Rhizome
Figure 7.3:Turmeric Powder
Curcuminoids: Chemistry
Isolation
The coloring principle of turmeric was isolated in the 19th century and called curcumin. Curcuminoids now refer to a group of phenolic compounds present in turmeric, which are chemically related to its principal ingredient curcumin. Three curcuminoids were isolated from turmeric viz., curcumin, demethoxycurcumin and bisdemethoxycurcumin (Figure 7.4) (Chattopadhyay et al., 2004).
Figure 7.4: Chemical Structures of Major Curcuminoids from C. longa
Curcumin, demethoxycurcumin, and bisdemethoxycurcumin have also been isolated from Curcuma managga (Abas et al., 2005), Curcuma zedoaria (Syu et al., 1998), Curcuma xanthorrhiza (Aggarwal et al., 2007), Curcuma aromatica, Curcuma phaeocaulis (Tohda et al., 2006), and other herbs like Costus speciosus (Aggarwal et al., 2007), Etlingera elatior (Mohamad et al., 2005), and Zingiber cassumunar (Aggarwal et al., 2007).
Considering the various biological activities of curcuminoids, attempts were made by several researchers in the past to isolate curcuminoids from turmeric rhizomes.
Rhizomes were extracted by using various techniques such as hydro-distillation, low-pressure solvent extraction, Soxhlet, and supercritical extraction using carbon dioxide. Extraction of curcuminoids involved prior extraction of rhizomes with hexane to remove much of the volatile and fatty components and then extracting with benzene. The concentrate was further purified by crystallization from ethanol to yield orange-yellow needles. But, the yield of curcuminoids was poor. The hot and cold percolation extraction methods gave good yields with a high recovery of curcuminoids. Alternatively, curcuminoids were extracted as insoluble lead salt (Jayaprakasha et al., 2005). Recently, extraction of curcuminoids using supercritical carbon dioxide modified by 10 per cent ethanol was also reported (Baumann et al., 2000). Although supercritical fluid extraction is known to be a clean technology giving acceptable yields and purity, its major disadvantage lies in its high operating pressures. The scale up problems could also be severe when the extraction is to be done in large scale. To avoid all these problems microwave assisted extraction (MAE) technique for selective and rapid extraction of curcuminoids is reported recently. Turmeric powder was irradiated with microwave showed marginally higher extraction of curcuminoids in 60 min by acetone. The feasibility of this technique has to be studied further for industrial applicability (Dandekar and Gaikar, 2002; Manzan et al., 2003).
Isolation of pure curcumin from plant material is time consuming and curcumins sold in the market is therefore, a purified extract containing a mixture of the three curcuminoids i.e, curcumin (75–81 per cent), demethoxycurcumin (15–19 per cent) and bisdemethoxycurcumin (2.2–6.6 per cent). The standardized C. longa extract or turmeric extract in the market is 95 per cent of all the three curcuminoids and much of the biological studies were on this extract (Composition).
Structure
Curcumin, C21H20O6, mp 184–185ºC was isolated as early as 1815. It is insoluble in water but soluble in ethanol and acetone. Daube obtained it in crystalline form. The structure of curcumin as a diferuloylmethane was confirmed by the degradative work and synthesis by Lampe in 1910 (Roughley and Whiting, 1973).
On boiling with alkali, curcumin gave vanillic acid and ferulic acids whose structures were established. Fusion with alkali yielded protocatechuic acid and oxidation with potassium permanganate yielded vanillin. On hydrogenation, mixtures of hexahydro–and tetrahydro-derivative were obtained and on acetylation gave diacetyl derivative. Based on these, the structure of curcumin was established as diferuloylmethane (Figure 7.4).
Synthesis
Heller isolated two products by condensation of acetyl acetone with vanillin in the presence of ethanolic hydrogen chloride. These two products differed by the reaction of boric acid and ferric chloride. Heller came to the conclusion that normal curcumin which gives deep reddish brown color with ferric chloride has the keto-enol structure, while the two products which gave only pale yellowish brown color have diketone structures and these forms being stereo isomers of the same structure. Recently, curcuminoids were synthesized in good yield from acetyl acetone and vanillin using boric oxide (Pabon, 1964; Pedersen et al., 1985; Babu and Rajasekharan, 1994).
Figure 7.5:Synthesis of Curcuminoids
Other Curcuminoids
Besides these major curcuminoids such as curcumin, demethoxycurcumin and bisdemethoxycurcumin five minor constituents are also isolated. One of these is cyclocurcumin, which was isolated from the mother liquor of Curcuma longa extract by repeated purification, as yellow gum (Kiuchi et al., 1993). 1-(4-Hydroxy-3,5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione has been isolated from rhizomes of Curcuma xanthorrihiza (Masuda et al., 1992; Venkateswarlu et al., 2004) (Figure 7.6).
Figure 7.6:Minor Curcuminoids from C. longa
Bisdemethylated curcumin was also present as minor constituent in the C. longa extract (Akio et al., 1993). Monodemethylated curcumin was isolated from Curcuma domestica (Nakayama et al., 1993). Recently, demethylated monodemethoxycurcumin (Figure 7.7) was also isolated from Curcuma longa as minor natural product (Jiang et al., 2006). The NCI group has synthesized bisdemethylated curcumin from curcumin and found that it is having good antiHIV activity than curcumin (Mazumder et al., 1997). Very recently, the curcumin mixture or standardized C. longa extract is converted into demethylated curcuminoid mixture having bisdemethylated curcumin (70–80 per cent by wt.), monodemethylated curcumin (2–8 per cent by wt.), demethylated monodemethoxycurcumin (10–20 per cent by wt.) and bisdemethoxycurcumin (0.5–2 per cent by wt.) by a simple procedure (Ganga Raju et al., 2007). They also found that this enriched demethylated curcuminoid mixture has strong antioxidant activity and has several fold potent activity than the curcuminoid mixture. Moreover, this demethylated curcuminoid mixture also exhibits potent 5-lipoxygenase inhibitory activity and has also several fold potent activity than the curcumin mixture.
Figure 7.7:Demethylated Analogs of Cucurminoids
Biological Activities
The use of Curcuma longa to treat a variety of inflammatory, biliary and respiratory disorders, has generated scientific interest in the curative properties of the turmeric rhizome. Much of the work has focused on the use of dried extracts, the volatile oil and the active principles, the curcuminoids.
Antioxidant Activity
Oxidation is the transfer of electrons from one atom to another and represents an essential part of aerobic life and in our metabolism, since oxygen is the ultimate electron acceptor in the electron flow system that produces energy in the form of ATP (Adenosine triphospate). The oxygen molecule is very stable in the ground state, but it is changed into reactive oxygen species (ROS), namely, superoxide ion (O2–1), peroxide radical (?OOH), hydroxyl radical (?OH) and nitric oxide (NO?) by the environmental pollutants, radiolysis, UV and the reduction pathway to H2O in the living tissues. These free radicals play a major role in the initiation and progression of a wide range of pathological diseases like cancer, Alzheimer’s, Parkinson’s and cardiovascular diseases. In the food industry, free radicals have been found to be responsible in the deterioration of foods during processing and storage. In view of this, considerable attention has been given to the addition of antioxidants in foods and supplementation of antioxidants to biological systems to scavenge free radicals.
The aging process exemplifies the cumulative result of deterioration of individual cells, tissues and organs, promoted by free radicals. The human body has built-in mechanisms to counteract free radicals. These mechanisms are collectively known as the body’s antioxidant defense mechanism. Unfortunately, in most instances, the antioxidant defense is gradually overwhelmed by the aging process, or a disease, or both. The inflammatory processes associated with microbial or viral infections and the progression of cancer are just a few disease conditions which contribute to depletion of the antioxidant defense system of the body. Therefore, it is important to preserve the body’s defenses against damages by free radicals. Some vitamins, minerals, and natural compounds such as phenolics, flavonoids and carotenoids, have the ability to counteract free radical damage by scavenging or neutralizing the free radicals. These diversified groups of nutrients, micronutrients and food supplements belong to a category of biologically important substances known as “antioxidants’.
The antioxidative compounds can be classified into two types: phenolics and β-diketones. Phenolic compounds exert their antioxidant activity by acting primarily as hydrogen atom donators, thereby inhibiting the propagation of radical chain reactions. Antioxidant potential of the phenolics depends on the number and arrangement of phenolic hydroxyl groups, as well as the nature of the other substituents on the aromatic rings. Few natural products, like curcuminoids have both phenolic and β-diketone groups in the same molecule and thus became potential antioxidants (Halliwell and Gutteridge, 1985; Larson, 1988).
Curcuminoids exhibit potent antioxidant properties and recent studies provide convincing evidence for the antioxidant properties of curcuminoids.
Both turmeric and curcuminoids inhibited generation of potent free radicals like superoxide and hydroxyl radicals (Reddy and Lokesh, 1992). The antioxidant properties of curcumin in prevention of lipid peroxidation, another process that generates free radicals, is well recognized (Sharma, 1976). Studies on spice principles as antioxidants in the inhibition of lipid peroxidation of rat liver microsomes revealed that curcumin was a potential antioxidant. Among the spice principles tested, curcumin showed the highest ability to prevent lipid peroxidation. Curcumin, in this study, was found to be eight times more potent than vitamin E.
Animals fed with curcumin showed decreased levels of lipid peroxides and subsequent reduction in the chemically induced inflammation (Sreejayan Rao, 1994). Thus, it is obvious from these studies that curcumin prevents the production of tissue-damaging free radicals. Also, under in vitro conditions, in tissue culture, rat and mouse liver cells incubated in the presence of micromolar concentrations of curcumin reduced the generation of lipid peroxides (Sharma et al., 1972). Curcumin also prevented the oxidative damage and alteration of the DNA genetic material in cultured fibroblasts (Shih and Lin, 1993).
A potential role of curcumin in preventing oxidative damage to the arterial wall has been studied. Cardiovascular disease is caused by the progressive narrowing of the arterial walls. This is essentially due to the deposition of cholesterol plaque inside the arterial walls resulting from high levels of oxidized cholesterol in the blood. Oxidation of blood cholesterol is evaluated in clinical studies by measuring blood levels of lipid peroxides. Administration of 500 mg of curcuminoids daily to healthy humans for seven days lowered the levels of blood lipid peroxides by 33 per cent, as well as the levels of blood cholesterol by 29 per cent. The authors of this study indicated possible use of curcuminoids in the prevention of cardiovascular disease (Soni and Kuttan, 1992).
An important corollary of the antioxidant action of curcuminoids in their potential use as natural food additives to prevent the oxidation and resultant rancidity of oils and fats during storage and heating.
In a recent research report (Sreejayan Rao, 1994), the inhibitory effect of lipid peroxidation by various curcuminoids was compared against a well-known antioxidant, vitamin E α-tocopherol). In this investigation, the lipid peroxidation in the biological materials was induced by the addition of ferrous sulfate (Fe+2), ferric chloride (Fe+3), Fe+3-ADP-ascorbate complex or Fe+3-ADP-NADPH complex. The results revealed that the curcuminoids were more potent inhibitors of experimentally induced lipid peroxidation than vitamin E α-tocopherol. All the three curcuminoids tested, curcumin, demethoxycurcumin, and bisdemethoxycurcumin were almost equally active. Very recently, curcuminoids and bisdemethylcurcumin were studied for their antioxidant activity by superoxide free radical (NBT) and DPPH free radical scavenging methods and found that curcuminoids are potent antioxidants when compared with the natural antioxidants like vitamine E, BHA, BHT and vitamin C. Interestingly, the bisdemethylcurcumin is several times more potent than the curcuminoids (Venkateswarlu et al., 2005).
The antioxidant mechanism of curcuminoids may include one or more of the following interactions:
1. Scavenging or neutralizing the free radicals
2. Interacting with oxidative cascade, and preventing its outcome
3. Oxygen quenching, and making it less available for oxidative reactions
4. Inhibition of oxidative enzymes like cytochrome P-450, and
5. Chelating or disarming oxidative properties of metal ions such as iron (Fe).
In conclusion, turmeric and its active constituents, curcumins or curcuminoids have antioxidant properties and effectively inhibit the free radical damage to biomolecules both in vitro and in vivo conditions. The fact that curcuminoids act as antioxidants by prevention and intervention processes, makes them very unique disease preventive agents (Anto et al., 1996).
Antiinflammatory A
Inflammation results from the complex series of actions and reactions triggered by the body?s immunological response to tissue damage. Many diseases as well as physical trauma, including surgery, induce inflammatory reactions. These reactions, although necessary to start the healing process, too often create an unbearably painful condition, which may even perpetuate the disease. Several inflammatory mediators, such as, histamine, eicosanoids, platelet activating factor, TNF etc are involved in the inflammation process.
Inflammation is an active part of many chronic disease states. Steroidal drugs like cortisone, and non-steroidal antiinflammatory drugs (NSAID) like phenylbutazone and indomethacin, are used in clinical practice to subdue the inflammation. Some of the antiinflammatory drugs inhibit the lipoxygenase pathway, and the other by cyclooxygenase pathway resulting in different potency and clinical applications for the antiinflammatory drugs. Two of the factors that are very active mediators in the inflammatory process are both derived from the fatty acid, arachidonic acid.
These are the leukotrienes, produced by 5-lipoxygenase (5-LOX) and the prostaglandins, produced by cyclooxygenase (COX). Currently, NSAID’s (non steroidal antiinflammatory drugs) are the primary therapy for many inflammatory diseases, e. g. rhematoid arthritism, osteoarthritis, periodontal disease etc. Unfortunately regular use of NSAID’s produce dangerous side effects such as changes in blood pressure levels and increases the development of ulcers of the stomach and duodenum (Samuelsson, 1983; Srimal and Dhawan, 1973).
Curcuminoids and other constituents of turmeric are well known for their antiinflammatory activity. Turmeric is one of the oldest antiinflammatory drugs used in Ayurvedic medicine. In fact, it was in India that the research on the antiinflammatory properties of turmeric was initiated. Turmeric extract, volatile oil from turmeric and curcuminoids were reported to possess antiinflammatory activity in different experimental models of inflammation in mice, rats, rabbits and pigeons. The antiinflammatory activity of turmeric and curcuminoids was evaluated in inflammatory reactions induced by chemical or physical irritants like carrageenin, cotton pellets, formaldehyde, and granuloma pouch technique.
Figure 7.8:Arachidonic Acid and Cascade
The antiinflammatory properties of curcuminoids were studied in carrageenin induced foot paw edema in mice and rats. The oral doses of curcumin required to reduce the inflammatory edema, or tissue swelling, to half the size (ED50–a dose effective in reducingedema by 50 per cent) are indicated below:
Species | ED50 Curcumin | ED50 Cortisone |
Mice | 48 mg/Kg | 45 mg/Kg |
Rats | 100.2 mg/Kg | 78 mg/Kg |
Utilizing cotton pellet and granuloma pouch tests in rats, both curcumin and non-steroidal drug, phenylbutazone, were effective at ED50 dose of 48 mg/Kg (Srinivas and Prabhakaran, 1989).
The antiinflammatory activity of curcumin was evaluated in a group of patients who underwent surgery or suffered from trauma. A double-blind placebo controlled trial in which three groups of patients received curcumin (400 mg), a placebo (250 mg of lactose powder) or phenylbutazone (100 mg) respectively, three times a day for five consecutive days after surgery (for hernia or hydrocele). The treatment with curcumin resulted in reduced inflammation and was as equally effective as the treatment with phenylbutazone. Turmeric has also been evaluated in the treatment of inflammation associated with various forms of arthritis. Oral administration of curcumin at a dose of 3 mg/kg and sodium curcumin at a dose of 0.1 mg/kg inhibited formalin-induced arthritis in rats. Curcumin was comparably effective to phenylbutazone in arresting formalin-induced arthritis in rats.
The antirheumatic properties of curcuminoids were tested in a double-blind clinical trial in 49 patients with diagnosed rheumatoid arthritis. Curcumin administered at a dose of 1200 mg/per day for five to six weeks, produced a significant improvement in all patients. All patients showed overall improvement in morning stiffness, and physical endurance. The therapeutic effects were comparable to those obtained with phenylbutazone (Majeed et al., 1995).
Turmeric was also used to treat patients with chronic respiratory disorders, with resulting subjective improvement of the condition and significant relief in symptoms like cough and dyspnea. Eye drops prepared from the decoction of turmeric, known as “Haridra Eye Drops”, were used in 25 cases of an inflammatory condition of the eye, bacterial conjunctivitis. Clinical symptoms such as eye redness or burning sensation, started subsiding from the third day of treatment. The cure rate evaluated during the six-day treatment was 23 out of 25 patients completely relieved from the condition (Ammon et al., 1993).
Curcumin and its four synthetic analogs were examined for antiinflammatory potential in carrageenin induced foot paw edema and cotton pellet granuloma models of inflammation on rats. The antiinflammatory potency of tested curcummin, curcumin analogs and phenylbutazone were established in the following order: sodium curcumin> tetrahydrocurcumin> curcumin> phenylbutazone and triethylcurcumin. Sodium salt of curcumin was effective at half the dose of the parent compound, curcumin. Comparison of curcumin and its analogs in acute and subacute models of inflammation revealed that curcumin analogs are more active in alleviating acute inflammation (Majeed et al., 1995).
One of the mechanisms understood for the antiinflammatory action of curcumins is its inhibition of cyclooxygenase and lipoxygenase enzymes (Huang et al., 1991). These enzyme inhibitions may be a result of diminishing inflammatory products of the arachidonic acid metabolism, e.g.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
