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Curcumin

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GENERAL FEATURES

Name: Curcumin
Generic Names: Diferuloylmethane[1], [2], [3], [4], [5], [6]
bis-α,β-unsaturated β-diketone[7]
Trade
Names:
Meriva®:[8]
BCM95, biocurcuin[9]
'Curcumin C3 complex'(a capsule contains 450mg curcumin, 30 mg of desmethoxycurcumin and 20 mg of bidesmethoxycurcumin)[10]
Commercial grade curcumin contains 77% curcumin, 17% demethoxycurcumin and 3% bisdemethoxycucrumin[11], [12], [13]
Super Bio-curcumin®:[13]
IUPAC
name:
1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione[14], [15], [16],[3], [17], [18], [19], [20], [21], [22], [6], [23], [24], [25], [26], [27], [28]
Molecular Weight: 368.37 gm/mol[29], [30]
Structure: [31], [1],[16], [32], [33], [30], [34], [35], [36], [37], [38], [39], [10], [40], [19], [41], [5], [20], [42], [43], [44], [45], [46], [22], [6], [47], [48], [49], [50], [40], [23],[51], [13], [52], [53], [54], [55], [25], [56], [57], [58], [27], [28]
Curcumin is a dicinnamoyl derivative with two conjugated dienes[47],[59],[60],[61]
Curcumin has three ionizable protons[15], has seven-carbon β-diketone linker, which responsible for its instability[62]
A study suggested that five-carbon linker analogue of curcumin containing cyclohexane ring may prove beneficial for developing anti-inflammatory curcumin drugs[62]
Structure of curcumin is planar except the two methylene and methoxy methyl hydrogens. The distance of methoxy oxygen and hydroxyl hydrogen is 2.05Ao [15]
The most predominant enol form of curcumin has three dissociable protons, the enolic one and the two equivalent phenolic ones[63]
Curcumin has two phenolic rings, each substituted with a methoxy ether functionality in the ortho-position. The two phenolic rings are joined via an aliphatic unsaturated heptene linker in the para-position that also contains an α, β diketonic functionality on carbon-3 and -5[43]
Curcumin has presence of π conjugation[64]
Curcumin is a bis-α,β-unsaturated β-diketone[29]
Functional Group: Possess phenolic hydroxy and β-diketone group,[65]
Ortho-methoxy group is important for curcumin’s antioxidant activity[7]
Curcumin acts as a Michael acceptor due to presence of α,β-unsaturated ketone moieties coupled with electron withdrawing phenolic hydroxyl groups[66]
Curcumin possesses two phenolic hydroxyl groups in its molecule[45]
Curcumin has aromatic ring conjugated with the double bond between 1 and 2 positions, 4-hydroxy, 3-methoxy groups and a 4-hydroxy group [21]
antioxidant activity of curcumin is believed to be due to presence of functional groups like methoxy, phenoxy, carbon-carbon double bonds in its structure[67]
methoxyphenol moiety in curcumin has one-electron reduction potential[23]
Has free hydroxyl groups on the benzene rings [40]
Two of the binding sites for Cu(II) on curcumin are provided by the intervening space between phenolic and methoxy groups on the two benzene rings and the third site exists owing to the presence of 1,3-diketone system between rings[39]
1,3-diketone moiety of curcumin is stable and chelates metal ions to scavenge active free-radicals[13]
The keto-enol-enolate equilibrium of the heptadienone moiety of curcumin determines its antioxidant property[23]
The presence of labile hydrogens on central CH2 group in heptadienone link of curcumin is important for hydrogen atom donating ability of curcumin[23]
The caffeic acid moiety of curcumin is found to be a potent in vitro inhibitor of lipid perixidation[20]
Removal of a methoxy group either at one phenyl ring or at both rings resulted in reduced 1O2 quenching activity [68]
Aromatic substituents and styryl ketone moiety are important 1O2 quenching activity[68]
Polyphenol moiety is suggested to be responsible for antioxidant effect of curcumin[69]
Curcumin contains two electrophilic α, β-unsaturated carbonyl groups[70]
Anti-oxidant activity of curcumin is due to phenolic OH group[16] and a small fraction may be due to the >CH2 site[15]
4-hydroxy-3-methoxyphenyl group plays role in antioxidant property of curcumin[16]
Chemical Nature: Hydophobic[64]
Crystalline in nature[71]
In neutral and acidic aqueous solutions (pH 3 to 7), the keto form of curcumin dominates[23]
Curcumin exists predominantly in enol form in solution[63]
hydrophobic polyphenol[61], [1]
Curcumin exists in equilibrium with its enol tautomer[29]
Lipophilic[72], diphenolic compound[73]
The maximum solubility of curcumin in the pH 7 buffer solution of HEPES is 25microM. Solubility of curcumin decreases rapidly with decreasing pH and in higher pH curcumin degrades very fast [74]
The stability of curcumin in aqueous solution is highly pH dependent[75]
Curcumin is insoluble in water at neutral pH. In slightly acidic media aand in the interior of cell membrane, curcumin exists in keto form, which favours H-atom transfer recations[23]
Curcumin is relatively insoluble in water but dissolves in acetone, dimethylsulphoxide and ethanol[29]
Samples containing curcumin should be protected from light as curcumin is light sensitive. Above pH 7, curcumin’s hue is less yellow and more red[29]
Melting point of curcumin is within 180-182oC[46] Melting point of curcumin is 183oC[29]
It exhibits keto-enol tautomerism, has predominant keto form in acidic and neutral solution and a stable enol form in alkaline media[61]
Less soluble in water but quite soluble in organic solvents such as dimethyl sulfoxide(DMSO), ethanol, methanol and acetone, has melting point of 183oC[30]
At pH 7.4, curcumin degrades rapidly in phosphate buffer and then degradation decreases drastically, showing a biphasic behavior[96]
Curcumin is unstable at neutral and basic pH and is degraded to ferulic acid and feruloylmethane[30]
Curcumin in insoluble in water[76], [37]
Curcumin produced radicals under alkaline conditions[77]
Curcumin is relatively unstable in phosphate buffer at pH 7.4[79] curcumin has low siolubility in saturated hydrocarbons[27]
Source: Isolated from dry rhizomes of spice turmeric(curcumin longa Linn)[1], [73], [3], [11]
Actions & Indications: Pharmcological Action-
Anti-oxidant[15], [51], [39]
pro-oxidant effect[39]
chain-terminating antioxidant[64]
Neuroprotective[2], [80]
Antilithogenic agent[135]
shows hypolipidemic effect[82]
anti-protein aggregation activity[80]
iron chelator[81]
anti-psoriatic[67]
anti-diabetic[67]
heat-shock response inducer[67]
anti-fibrotic[67]
anti-metastatic, anti-angiogenic[6]
Therapeutic benefits/Indications:
Anti-cancer[29] Anti-inflammatory[29], [2], [3], [67]
Immunopotentiator[83], immunomodulator[84]
Preclinica Data:
Pretreatment wth curcumin restored normal levels of liver cytokines IL-1alpha, IL-1beta, IL-2, IL-6 and IL-10[6]
Curcumin inhibited LPS-induced expression of COX-2 , which contributed to decrease formation of Prostaglandin E2 in murine macrophage RAW264.7 cells[53]
Curcumin in diet prevented galactose-induced cataract in Sprague-Dawley rats in vivo[85]
Curcumin suppressed LPS-induced iNOS expression and recovered eNOS levels in cultured rat mammary gland[86]
Curcumin decreased LPS-induced iNOS expression in activated macrophages; however curcumin in irradiated LPS activated macrophagesdid not decrease iNOS expression[87]
Dietary curcumin administered administered chronically to aged Tg2576 APPsw mice or acutely to LPS-injected to wild type C57BL6/J mice decrased interleukin-1β, and reduced LPS-stimulated iNOS, nitrotyrosine, F2 isoprostanes and carbonyls[88]
Curcumin(5 and 10mg/kg, PO) produced anti-depressant like effect in mice in vivo[89]
According to a cell culture and animal data, Curcumin can be effective in age-related neurodegenerative diseases like Alzheimer’s , parkinson’s and stroke[80]
Oral curcumin reduced malarial parasitic infection in mice [90]
Curcumin has sperm-immobilization effect hence it can be a potent intravaginal spermicidal agent for contraception[91]
Curcumin(40mg/kg, IP) could enhance the healing punch wounds faster in male Swiss albino rats and guinea pigs in vivo[92]
Curcumin demonstrated to be a potential agent in chemotherapy and chemoprevention of leukemia due to its ability to block stromal protection and hence prevent resistance to chemotherapy[83]
Curcumin was found to have trypanocidal activity in vitro[93]
Curcumin protects mitochondria and primary cultured rat cortical neurons against oxidative damage[44]
Curcumin(75 mg/kg/day)prevented experimental alcoholic liver disease in rat model[94]
Curcumin-induced improvement in neuropathological deficits in CAG 140 knock-in mice, suggested a beneficial role of dietary curcumin in Huntington’s disease[95]
Curcumin is reported to prevent induction of hyperplastic nodules, body weight loss and hypoproteinemia in carcinogen induced and xenograft hepatic cancer models[61]
curcumin inhibited arachidonic acid-induced inflammation in vivo in mouse skin[40]
curcumin protected against renal interstitial inflammation and renal fibrosis due to ureteral occlusion in adult male rats in vivo[97]
curcumin prevented adverse changes in dendritic morphology of CA3 pyrimidal neuron in hippocampal region of Sprague-Dawley rats in vivo and thus could be considered as effective in nullifying learning and memory disturbances[98]
curcumin may have beneficial effect in diseases like inflammation, obesity, diabetes and atherosclerosis in which hyperlipidemia plays a role[82]
pre-treatment with curcumin attenuated ischemia-reperfusion-induced liver injury in rats in vivo[99]
curcuma (100mg/kg, PO) caused decrease in lead-induced lipid peroxidation, neurotoxicity and increased antioxidant enzyme levels in all brain regions of rats[100]
curcumin inhibited growth of Helicobacter pylori cagA+ strains in vitro[101]
curcumin(0.5%) reduced the incidence of cholesterol gallstone in hamsters in vivo[135], curcumin(0.5%) for 5 weeks in male mice caused regression of pre-established cholesterol gallstone[102]
curcumin could suppress erythroleukemia induced by Friend virus(FMuLv) in BALB/c mice[103]
curcumin 2.5g/day in a patient exhibited strong anti-HIV activity[105]
curcumin could protect against arsenic-induced toxicity and DNA damage in population of West Bengal[106]
curcumin exhibited fungicidal activity against phytopathogenic fungi[107]
Curcumin(10microM) induced senescence in human colon cancer cells(HCT116) in vitro[108]
Curcumin is proved to be effective in preventing cognitive deficits and treatment of sporadic dementia of Alzheimer’s type(SDAT) in rat model[109]
Curcumin to lambda cyhalothrin-intoxicated rats decreased lipid peroxidation and DNA fragmentation in liver tissue[110]
Curcumin facilitated early suppression of paraquat-induced lung injury in rats in vivo[111]
Curcumin(15 or 20microns) inhibited O-tetradecanoyl-phorbol-13-acetate(TPA)-induced protein kinase C activity in mouse fibroblast cells(NIH 3T3)[112]
Curcumin is proposed to be of use to correct cystic fibrosis defects in humans[113]
Chronic administration of curcumin(1.25, 2.5, 5 and 10mg/kg, PO) exhibited antidepressant effect in forced swim and olfactory bulbectomy models of depression in rats[114]
Curcumin exhibited cytotoxic activity(anti-parasitic) against leishmania in vitro[115]
Curcumin partially mitigated severe neuropathy phenotype of Trembler-J mouse model and improved motor performance, suggesting a potential role of curcumin in selected forms of inherited peripheral neuropathies[116]
Curcumin
analogues/
curcuminoids:
Cu(II)-Curcumin complex (stoichiometry 1:1 and 1:2) shows electron and hydrogen atom transfer reactions with free radicals and produce phenoxyl radicals [117]
Cu(II)-curcumin complex (1:1) has larger distortion from square planar geometry which made it exhibit higher superoxide dismutase activity(SOD) and better superoxide anion radical scavenger(proton transfer and electron transfer, but less active in scavenging DPPH radical(H-atom transfer) than Cu(II)-curcumin complex(1:2). Both complexes (10 microM)inhibited lipid peroxidation in liposomes at absorbed doses of 210, 420 and 630 Gy[117]
Curcumin semicarbazone exhibited enhanced antiproliferation of MCF-7 breast cancer cells in vitro[33]
Curcuminoids(demethoxycurcumin, bisdemethylcurcumin) can bind to sequences of AT base pairs and degrade DNA. These curcuminoid could generate hydroxyl radical as well as inhibit the hydroxyl radical-induced damage to supercoiled plasmid DNA[39]
Curcumin analogues exhibited antioxidant activity in linoleic acid in micelles and reduced lipid-peroxidation in micelle by H-atom abstraction[18]
Curcumin and its analogues are found to be effective antioxidant against AAPH- and Cu+2-induced low density lipoprotein(LDL) peroxidation and H-atom abstraction from phenolic activity of curcumin[19]
Manganese complex of curcumin protected brain lipids in vitro against peroxidation, inhibited H2O2-induced cell damage in NG108-15 cells[118]
Manganese complex of curcumin showed to be effective HO* scavenger[119]
Demethylated derivative of curcumin viz. bis-3,4-dihydroxycinnamoylmethane is found to be the potent inhibitor of lipid peroxidation of rat brain in vitro[20]
Synthetic analogue of curcumin(BDMC-A) protects lung of male Wistar albino rats against nicotine-induced lipid peroxidation[120]
Curcuminoids decreased superoxide radical formation leading to lowering of hydrogen peroxide in cellular environment of normal human skin keratinocytes[121]
Pretreatment with curcumin analogues, bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione , protected isolated rat hepatocytes in vitro against gamma-radiation induced cellular, DNA damage, lipid peroxidation and enzymic and non-enzymic antioxidant loss[48]
Synthetic nonphenolic curcuminoids did not exhibit antioxidant activity[24]
Curcumin resistance: Chk1-mediated G2/M arrest in hepatoma cells in vitro is said to be a mechanism for curcumin resistance. Apoptosis in curcumin resistant cells after Chk1 depletion is induced by “Bad”.[122]
Sensitivity of cancer cells to curcumin can be correlated to generation of superoxide radical. Curcumin-resistant cancel cells showed significant increase in hsp70 expression, hence mounting a stress response and protects cell from apoptosis[26]
Cells resistant to curcumin(50 microM for 24 hrs):
Cell lines from lung(A 549), kidney(A 498), prostate(DU 145), cervix(HeLa), CNS malignancies(SF-268), and melanoma(SK-MEL, M-14), ovarian(PA-1) and colon (SW620) cell lines[26]
Cell sensitive to cytotoxic action of curcumin(50microM for 24 hrs):
Leukemia(HL-60, K-562, CCRF-CEM, JURKAT), breast, colon, hepatocellular(Hep G2) and ovarian carcinoma, cell lines of reticuloendothelial origin, (COLO-205)colon, (MDAMB)breast, (OVCAR 8)ovarian cell lines[26]
Notes: Curcumin was found to be more stable in cell culture medium containing 10% fetal calf serum and in human blood[30]
Curcumin is on the FDA’s GRAS(generally recognized as safe)list [123]
When kept after dissolution in HPLC injection solvent (acetonitrile:water 1:1) , curcumin and its metabolites were found to be stale for at least 12 h at room temperature[10]
Vanillin, ferulic acid and a dimer of curcumin were found to be curcumin-derived radical reaction products[124]
Curcumin is generally used as dissolved in 0.5% DMSO or cottonseed oil for oxidative damage and radiomodification experiments in vivo and in vitro[125],[48], [126], [127], [128]
Bio-availability improvement of curcumin, following approaches were taken:
1. Use of adjuvants like piperine that interferes with glucuronidation
2. The use of liposomal curcumin
3. Use of curcumin nanoparticle
4. Use of curcumin phospholipid complex
5. Use of structural analogue of curcumin[13][61]
It is suggested that curcumin induces a mild oxidative and lipid-metabolic stress leading to an adaptive stress response by hermetic stimulation of cellular antioxidant systems and lipid metabolic enzymes[82]
It is suggested that bioactive degradation products of curcumin also contribute to pharmacological effect of curcumin against Alzheimer’s disease and cancer [129]
Energy transfer between curcumin and both tyrosine and tryptophan residues of BSA, is enhanced in the presence of SDS[130]
Curcumin in 0.1M phosphate buffer and serum-free medium, pH 7.2 at 37oC(at physiological conditions in vitro), about 90% decomposed within 30 mins.[131]
It is more stable in cell culture medium containing 10% fetal calf serum and in human blood, less than 20% of curcumin decomposed within 1 hand aftr 8 h, 50% of curcumin remains[131]
Curcumin degrades rapidly in serum-free medium hence precautions must be taken while cell culture experiments with curcumin[131]
curcumin, even at doses as high as 8g/day, is not found to be associated with any adverse effects[60]
Limitations: curcumin exhibits low serum levels, limites tissue distribution, rapid metabolism and short half-life.[61]
Curcumin is insoluble in aqueous solutions and hence has poor bioavailability. Bioavaibility of curcumin can be enhanced by increasing the solubility of curcumin with the use of heat[132] and its implementation is suggested to be considered in curcumin clinical trials[133]
Curcumin is suggested to exhibit limited non-specific toxicity towards non-cancerous cells[134]
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