CURCUMIN: TRANSFORMING THE SPICE TO A WONDER DRUGHTML Full Text
CURCUMIN: TRANSFORMING THE SPICE TO A WONDER DRUG
Geetha Elias*, P Jaismy Jacob, E Hareeshbabu, V Baldwin Mathew, Bibitha Krishnan and K. Krishnakumar
Department of Pharmaceutical Chemistry, St. James’ College of Pharmaceutical Sciences, Chalakudy, Kerala- 680307, India
ABSTRACT: Turmeric is a spice obtained from the dried rhizomes of Curcuma longa, family Zingiberaceae. It has been extensively used in traditional Indian (Ayurveda) and Chinese medicine for various ailments such as anti-inflammatory, blood purifier and even as a cosmetic. Curcumin, the chief constituent in turmeric has been isolated centuries ago, has been found to have a wide range of pharmacological actions such as antioxidant, anti-inflammatory, anticancer, antimicrobial and much more. Thus curcumin and its analogues have immense therapeutic potential for use in rheumatoid arthritis, Crohn’s disease, cancer, diabetes, cardiovascular disease, HIV-I and Alzheimer’s disease. Phase I clinical studies have shown that high doses of curcumin is well tolerated in man. Despite its safety, curcumin still evades clinical use due to poor bioavailability. Novel formulations of curcumin with piperine, soluble fibres of fenugreek, liposomes, micelles, nanoparticles, cyclodextrin and turmerone have shown enhanced bioavailability to some extent, each one having its own limitations. Recent formulation of curcuminoid with 45% turmerone seems to be promising. Further research in this direction is imperative to realize the clinical use of this promising molecule.
INTRODUCTION: The age old spice, turmeric contains 5% of curcuminoids and 6% essential oil as the yellow colouring matter. Curcumin, the chief constituent makes up 60% of curcuminoid 1, others are demethoxycurcumin, bisdemethoxycurcumin and AR- turmerone 1. Curcumin, a hydrophobic, polyphenol called diferuloylmethane is an antioxidant more powerful than alpha- tocopherol 2.
Turmeric has been used traditionally as antiinflammatory, stomachic, choleretic, cholagogue, blood purifier and as cosmetic 1. Extensive research has revealed that curcumin acts on multiple molecular targets, receptors, proinflammatory enzymes, protein kinases, adhesion molecules, transcription factors, antiapoptotic proteins and cell cycle-related gene expression 3. Modulation of these targets is the basis of numerous pharmacological actions such as antioxidant 1, anti-inflammatory 4, antimicrobial 5, 6, 7, anticancer 8, hepatoprotective 9, antidiabetic 10, antithrombotic11, anti HIV-I12 and in Alzheimer’s disease13. Three different clinical trials indicate that curcumin is well tolerated in man at doses as high as 12g/day 14. This review intends to have an overview of curcumin chemistry, structure - activity relationship, molecular targets, pharmacological actions, problems of bioavailability and various curcumin formulations designed to achieve improved bioavailability so as to realize the safe clinical use of this versatile molecule.
Chemistry &Structure-Activity Relationships (SAR) of Curcuminoids:
Curcuminoids, the main components in Curcuma species, share a common unsaturated alkyl- linked biphenyl structural feature and are responsible for their major pharmacological effects.
Curcumin,the chief constituent of curcuminoids is an orange–yellow crystalline powder practically insoluble in water and ether but soluble in ethanol, dimethylsulfoxide and acetone. Curcumin is 1, 6-heptadiene - 3, 5 – dione - 1, 7 – bis (4-hydroxy-3-methoxyphenyl)-(1E, 6E) or Diferuloylmethane. The feruloylmethane skeleton of curcumin was confirmed in 1910 by Lampe 15, 16.
Chemically, curcumin is a bis-α, β-unsaturated β-diketone and exists in equilibrium with its enol tautomer (Fig. 1). The bis-keto form predominates in acidic and neutral aqueous solutions as well as in the cell membrane due to the heptadienone linkage between two methoxyphenol rings containing a highly activated carbon atom.Curcumin has a unique conjugated structure including two methylated phenols linked by the enol form of a heptadiene-3,5-diketone that gives the compound a bright yellow color 17.
FIG. 1: KETO-ENOLTAUTOMERISM IN CURCUMIN.
Curcuminoids in C.longa and other Curcuma species are mainly curcumin, bis-demethoxycurcumin and demethoxycurcumin (Fig. 2), among which curcumin is the most studied and shows a broad range of biological activities.
FIG. 2: CURCUMINOIDS IN C. LONGA
Synthetic bioactive curcumin analogs were developed from the natural compound based on the structure-activity relationship (SAR) studies and optimization of compounds as drug candidates in their relation to different activities, including anti-inflammatory, anti-oxidant, anti-HIV and anti-cancer, as well as possible mechanisms of actions.
FIG. 3: BASIC NUCLEUS OF CURCUMIN
Structural possibilities for modification of curcumin - Aryl side chain modification (A), Modification of diketo functionality (B), Modification of double bond (C), Modification of active methylene functionality (D), Metal complexes of curcumin (E) and Appended curcumin mimics/structural analogs of curcumin (F).
The active constituents of C. Longa are curcuminoids, including curcumin, demethoxycurcumin and bisdemethoxycurcumin18 (Fig.1), among which curcumin is the most potent anti-inflammatory agent 19. In addition to these natural curcuminoids, sodium curcuminate and tetrahydrocurcumin (Fig. 4) showed potent anti-inflammatory activity at low doses in carrageenin-induced rat paw edema and cotton pellet granuloma assays 20. Other semi-synthetic analogs of curcumin were screened for anti-inflammatory activity in the same assays; diacetylcurcumin and tetrabromocurcumin (Fig. 4) were the most potent 21, 22, 23. The presence of the β-diketone moiety as a linker between the two phenyl groups was deemed important for the anti-inflammatory activity.
FIG. 4: STRUCTURES OF SEMI-SYNTHETIC ANALOGS TESTED FOR ANTI-INFLAMMATORY ACTIVITY
It was found that the phenolic analogs were more active than the non- phenolic analogs 24. The highest antioxidant activity was obtained when the phenolic group was sterically hindered by the introduction of two methyl groups at the ortho position. The phenolic group is essential for free radical scavenging activity, and the presence of the methoxy group further increases the activity 25. The structural features that enhance the antioxidant properties of phenols are optimized in curcumin to a significant extent 24. Curcumin and tetrahydrocurcumin had the strongest anti-oxidant activity among the natural and hydrogenated curcuminoids respectively 26, 27, 28. Among all compounds, tetrahydrocurcumin showed the highest potency, implying that hydrogenation of curcuminoids increased their anti-oxidant ability. Absence of one or both methoxy groups resulted in decreased anti-oxidant activity in both natural curcuminoids and tetrahydrocurcuminoids. Tetrahydrocurcumin and curcumin showed comparable antioxidant activity. This result suggests that enhanced electron delocalization of the double bonds may not be essential to anti-oxidant activity of curcuminoids.
Simon etal 29, found that the presence of the diketone moiety in the curcumin molecule seems to be essential for its ability to inhibit the proliferation of MCF-7human breast tumor cells. The aromatic enone and dienone analogs of curcumin were demonstrated to have potent antiangiogenic properties in an in vitro SVR assay 30.
Certain curcumin analogs including 1 (JC-9), 2 (4-methoxycarbonyl curcumin, MCECu) and 3 (LL-80) showed potent in vitro cytotoxic activity against LNCaP and PC-3 human prostate cancer cell lines (Table1). Among them, compound 4 showed the most potent activity, suggesting that introducing a conjugated side chain in the enol-ketone linker may stabilize the enol-ketone form as the predominant tautomer, which may contribute to the anti-prostate cancer activity 32.
TABLE 1: CYTOTOXIC ACTIVITY DATA OF CURCUMIN DERIVATIVES AGAINST PC-3 AND LNCAP PROSTATE CANCER CELL LINES
|Compound||R1||R2||PC-3 IC50 (μM)*||LNCaP IC50 (μM)*|
IC50 values are mean concentrations that inhibit cell growth by 50% (variation between replicates was less than 5%).
IC50 values are expressed as 'means'.
It has been found that curcumin loses its activity instantaneously in a reducing environment. Enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 5) and pyrazole (compound 6) groups. Isoxazole and pyrazolecurcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Molecular modeling has shown that both compounds 5 and 6 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 5 and 6 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 5 and 6 could be good replacements for curcumin in future drug development 32.
FIG. 5: SYNTHETIC CURCUMIN ANALOGUES HAVING ANTICANCER ACTIVITY
FIG. 6: SCHEMATIC DIAGRAM OF STRUCTURAL FEATURES FAVOURING ANTI-HIV-1 INTEGRASE ACTIVITY 33.
In the further SAR investigation of curcumin analogs as inhibitors of HIV-1 integrase, a syn disposition of the C=C-C=O moiety in the linker and a coplanar structure were found to be important to the integrase inhibitory activity of curcumin analogs 34.
Curcumin’s capacity to modulate multiple molecular targets forms the basis of its numerous pharmacological actions such as antioxidant 1,anti-inflammatory 4, anticancer 8, nephro& hepatoprotective 9, cardioprotective 35, antidiabetic 10 and antirheumaticactions 36. It has also been found to be effective in Alzheimer’s disease 13 and against HIV-I 12.
Antiinflammatory and antioxidant properties:
Curcumin has been found to be a potent antioxidant37 and anti-inflammatory agent4. Curcumin has been shown to suppress the expression of COX 2, 5-LOX, and iNOS that are pro inflammatory enzymes through suppression of transcription factor, NF-kB. Curcumin inhibits inflammation by blocking the adhesionof monocytes to endothelial cells by inhibiting the activation of the cell adhesion molecules ICAM-1, VCAM-1, and ELAM-1 3 Most of the activities of curcumin seem to be due to its ability to suppress inflammation 38.Free-radical-mediated peroxidation of membrane lipids, oxidative damage of DNA and proteins and inflammation 39, 40 are associated with a variety of chronic pathological conditions such as cancer, atherosclerosis, and neurodegenerative diseases. Hence curcumin is thought to play a vital role against these pathological conditions 38. Curcumin also functions as a pro-oxidant under certain conditions41 most likely as a result of electrontransfer to molecular oxygen to generate reactive oxygen species(ROS)42.
Multiple studies have shown that curcumin can reduce the growth of cancerous cells in the laboratory and inhibit the growth of tumors in test animals 43, 44. Curcumin has been shown to inhibit the proliferation of a wide variety of tumor cells, through suppression of various transcription factors including NF-κB, STAT3, Egr-1, AP-1, PPAR-γ, and betacatenin activation. Suppression of protein kinases, induction of apoptosis and modulation of cell- cycle related gene expression are other mechanisms for its anticancer action 3.
Cardio protective action:
Endothelial dysfunction is the underlying cause of heart diseases. Curcumin has been found to improve the functions of the endothelium thereby exerting cardio protective action 45.
Anti – Diabetic action:
Curcumin has shown beneficial effects in diabetic rats3.
There are many different types of arthritis, most of which involve inflammation of joints. Curcumin being a potent anti-inflammatory agent could alleviate rheumatoid arthritis46.
Oxidative damage, inflammation, cognitive deficits, and amyloid accumulation associated with Alzheimer’s disease are suppressed by curcumin47.
Anti HIV-I action:
Curcumin was found to be a potent and selective inhibitor of human immunodeficiency virus (HIV-1) long-terminal repeat-directed gene expression, which governs the transcription of type 1 HIV-1 provirus 48.
Nephro and hepato –protective action:
Curcuminoids have shown nephro and hepatoprotective action 49.
In-vitro studies have shown that curcumin has strong intrinsic activity and efficacy on various disease targets. However, unfavourable pharmacokinetic properties, particularly poor bioavailability have been identified as the major hurdle in approving it as a therapeutic agent. Poor absorption, inadequate tissue distribution, rapid first pass metabolism in the liver and intestinal wall 50, and short half life are the factors that result in extremely low serum and tissue levels.
Several bioavailability studies have shown that curcumin was poorly absorbed from the gut and higher serum levels were attained when curcumin was administered by i.p route in rodents than the oral route. However, data from human clinical trials suggest the role of initial oral dose on achievable serum levels of curcumin50, 51, 14, 52.
Irrespective of the dose, the percentage of curcumin absorbed (60-66% of the given dose) remained constant 53, 54. The serum levels of curcumin in rats and in human are not directly comparable. When curcumin was administered in mice by i.p route, maximum amount was seen in intestine, moderate amounts in spleen, liver and kidney, only trace amount was found in brain55, 56.
Various studies have evaluated the metabolism of curcumin in rodents and in humans. Once absorbed, curcumin is subjected to conjugations like sulfation and glucuronidation at various tissue sites. The first bio distribution study reported the metabolism of major part of curcumin orally administered to rats. Liver was indicated as the major organ responsible for metabolism of curcumin51, 57, 58. Holder et al. reported that the major billiary metabolites of curcumin are glucuronides of tetrahydrocurcumin (THC) and hexahydrocurcumin (HHC) in rats. A minor biliary metabolite was dihydroferulic acid together with traces of ferulic acid 59.
In addition to glucuronides, sulfate conjugates were found in the urine of curcumin treated rats53. Hydrolysis of plasma samples with glucuronidase by Pan et al. Showed that 99% of curcumin in plasma was present as glucuronide conjugates. Curcumin is absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide/sulfate conjugates 60, 61. Curcumin sulfate and curcuminglucuronide were identified in the colorectal tissue of colorectal cancer patients who ingested curcumin capsules 57, 58.
FIG. 7: METABOLITES OF CURCUMIN
The pharmacokinetics of curcumin has been extensively studied in animals, but to a lesser extent in humans. Majority of the studies have demonstrated that curcumin exhibits extremely poor gastrointestinal absorption/ oral bioavailability and undergoes metabolism to form several chemical species, including curcuminglucuronide and curcumin sulfate62.Attempts to avoid rapid metabolism has met with little success. Further research is warranted in this direction as available literature is unable to give clear evidence.
Measures to improve bioavailability:
Considerable effort has been taken to develop curcumin derivatives, curcumin analogs, and curcumin-drug vehicle combinations that display enhanced absorption and systemic bioavailability as compared to the parent drug 62. Large number of cucumin derivatives and curcumin analogues have been synthesized. Some of them have higher activities while others are less active than curcumin at the multiple molecular targets. However, there is no published data available on the specific bioavailability studies in humans for any of the synthetic derivatives of curcumin. Further research needs to focus on human bioavailability studies of the more active curcumin analogues in which the diketone moiety is replaced by isoxazole and pyrazole 34.
Attempts have also been made to use adjuvants, which can block metabolic pathways of curcumin, so as to improve its bioavailability. Nanoparticles, liposomes, micelles, phospholipid complexes and cyclodextrin complexes are other promising novel formulations, designed to sustain desired serum levels,improve tissue permeability and resist metabolic processes.
When combined with piperine, the bioavailability of curcumin increased 2000% in humans as compared to only 154% in rats. Piperine is known to inhibit hepatic and intestinal glucuronidation 63. When combined with piperine, the clearance of curcumin was significantly decreased. Hence the effect of piperine on bioavailability of curcumin is much greater in humans than in rats 64. Piperine may have an inhibitory effect in metabolism of other drugs that are detoxified by glucuronidation thus increasing their toxicity.
BCM-95 (also called Biocurcumax), a formulation of curcuminoid with essential oil of turmeric enhanced the bioavailability of curcumin and augmented the biological activity of curcumin in humans, where curcumin is the main constituent of curcuminoid and Ar-turmerone is the main constituent, 45% of the essential oil of turmeric65. This study stands apart as the enhanced bioavailability of curcumin has been demonstrated in human volunteers.
FIG. 8: AUC OF BIOCURCUMAX
Enhancement of bioavailability of the curcumin ranges from about 5-fold to about 16-fold 65. Biocurcumax has the additional benefit that the essential oil components are themselves bioactive and thus are expected to synergistically enhance the bioactivity of curcumin 66. AUC was 7–8 times higher when curcumin was combined with turmeric oil. Hence this formulation holds promise for clinical use in humans 67, 68.
A new fenugreek derived polysaccharide (referred to as galactomannans) containing fenugreek proteins was found to enhance the bioavailability of curcumin both in preclinical studies and in studies on human volunteers when formulated as amorphous microgranulate dispersions with proper molecular binding with curcuminoids. Fenugreek polysaccharide used in the present invention is non digestible, but swell extensively in the intestine and form a gel matrix in which curcumin is impregnated and leaches out very slowly. The advantage of the present formulation of micro granulate is that when consumed, it is very stable under physiological conditions and protect curcumin from easy access to enzymes responsible for its rapid degradation 69. This formulation enhances bioavailability without inhibition of glucuronidation. Whether this promising formulation provides optimum concentration at tissue levels is yet to be studied.
A polymer based nanoparticle of curcumin namely ‘‘nanocurcumin’’ was found to overcome the problem of poor aqueous solubility to some extentas reported recently. Nanocurcumin was found to have in vitro activity similar to that of free curcumin in pancreatic cancer cell lines70.However no in-vivo studies are reported with nanocurcumin. An in vivo study with healthy volunteers showed improved efficiency of a topical application cream containing curcuminoid loaded solid lipid nanoparticles (SLNs) over that containing free curcuminoids 71. Further in-vivo studies on nanoparticle based formulations is warranted in humans.
Liposomes are excellent drug delivery systems as they can carry both hydrophilic and hydrophobic molecules. Liposomal curcumin suppressed the pancreatic carcinoma growth in murine xenograft models and inhibited tumor angiogenesis 72. The efficacy of liposomal curcumin was compared with that of oxaliplatin, a standard chemotherapeutic agent for colorectal cancer. Liposomal curcumin exhibited greaterin-vitro and in-vivo activity than oxaliplatin. Liposomal curcumin is currently being developed for introduction into the clinical setting73. Studies have shown that liposomal vehicle is capable of loading more curcumin in to cells than either HSA or aqueous-DMSO, and lymphoma cells showed preferential uptake of curcumin to lymphocytes 74. However studies are yet to prove enhancement of bioavailability by liposomal curcumin.
Micelles and phospholipid complexes:
Micelles and phospholipid complexes can improve the gastrointestinal absorption of natural drugs, thereby giving higher plasma levels and enhance the bioavailability due to lower kinetic elimination. Further, the in-vitro intestinal absorption of curcumin was found to increase from 47% to 56% when the same was present in micelles75.A polymeric micellar curcumin gave a 60-fold higher biological half-life for curcumin in rats compared to curcumin solubilized in a mixture of DMA, PEG and dextrose 76.
Curcumin-phospholipid complex formation showed a significant improvement in curcumin bioavailability77. Curcumin formulated with phosphatidylcholine (Meriva) was given by oral gavage. Peak plasma levels for parent curcumin after administration of Meriva were 5-fold higher than the equivalent values seen after unformulated curcumin dosing. A 13 × 10 5 fold increase in curcumin solubility in a polymeric micellar formulation containingmethoxy poly (ethylene glycol)-block-polycaprolactonediblock copolymers (MePEG-b-PCL) 78. The enormous increase in solubility of curcumin in the above said micelle is very encouraging to continue further studies on the same.
Several attempts have been made to design water soluble and stable complexes formed from cyclodextrin and curcumin. Cyclodextrins are cyclic oligosaccharides consisting of α-(1-4)-linked glucopyranose units, which form a lipophilic cavity and a hydrophilic outer surface. Their non polar cavity is able to include hydrophobic molecules by non-covalent forces and thereby improve their water solubility. These formulations give hope for use in several critical conditions where it is necessary to give curcumin by parenteral routes. A novel cyclodextrin complex of curcumin (CDC) was found to be more active than free curcumin for antiproliferative and anti-inflammatory activities.
Compared with free curcumin, CDC had a greater cellular uptake and longer half-life in the cells. This novel complex is soluble at much higher curcumin concentrations. Only a low molar excess of cyclodextrin is required for the formation of this complex, which reduces the risk of adverse effects of cyclodextrins when administered at high doses79.
CONCLUSION: Despite the low toxicity and enormous therapeutic potential of curcumin, its effective clinical use still remains a distant dream. The pharmacokinetic parameters of the parent drug remain a significant challenge to widespread clinical use of curcumin for the treatment of many human diseases. Several clinical trials in humans have found that oral and even intravenous administration of free curcumin have been ineffective in achieving significant concentration of curcumin in any tissue due to rapid metabolism in gastrointestinal tract and in circulation. There is urgent need to design delivery systems for use through different routes that would achieve optimum drug concentrations in various tissues to elicit desired pharmacological actions in clinical settings.
Tremendous amount of promising work is being conducted to overcome this problem through the utilization of unique delivery systems and chemical modifications. Some curcumin formulations reviewed here that are particularly promising are Biocurcumax, curcumin-fenugreek galactomannan, and novel cyclodextrin complex (CDC).
ACKNOWLEDGMENT: The authors wish to thank St. James’ College of Pharmaceutical Sciences for providing facilities to prepare this manuscript.
- Biren Shah and Seth AK: Textbook of Pharmacognosy & Phytochemistry, Elsevier, First Edition 2009; 340.
- Sreejayan and Rao MNA: Curcuminoids as potent inhibitors of lipid peroxidation. Journal of Pharmacy and Pharmacology 1994; 46:1013–1016.
- Aggarwal BB, Kumar A and Aggarwal MS: Curcumin derived from turmeric (Curcuma longa): a spice for all seasons. In Phytochemicals in Cancer Chemoprevention. PD Debasis Bagchi & HG Preuss: CRC Press, New York, Edition 2005; 349–387.
- Srimal RC and Dhawan BN: Pharmacology of diferuloyl methane (curcumin), a non-steroidal antiinflammatory agent. Journal of Pharmacy and Pharmacology 1973; 25(6): 447–452.
- Reddy RC, Vatsala PG, Keshamouni VG, Padmanaban G and Rangarajan PN: Curcumin for malaria therapy. Biochemical and Biophysical Research Communications2005; 326 (2): 472–474.
- Kim MK, Choi GJ and Lee HS: Fungicidal property of Curcuma longa rhizome-derived curcumin against phytopathogenic fungi in a greenhouse. Journal of Agricultural and Food Chemistry2003; 51(6):1578–1581.
- Mahady GB, Pendland SL, Yun G and Lu ZZ: Turmeric (Curcuma longa) and curcumin inhibit the growth of Helicobacter pylori, a group 1 carcinogen. Anticancer Research2002; 22 (6C): 4179–4181.
- Kuttan R, Bhanumathy P, Nirmala K and George MC: Potential anticancer activity of turmeric (Curcuma longa). Cancer Letters 1985; 29(2): 197–202.
- Kiso Y, Suzuki Y, Watanabe N, Oshima Y and Hikino H: Antihepatotoxicprinciples of Curcuma longa PlantaMedica1983; 49(3): 185–187.
- Srinivasan M: Effect of curcumin on blood sugar as seen in adiabetic subject. Indian Journal of Medical Sciences1972; 26(4): 269–270.
- Srivastava R, Dikshit M, Srimal RC and Dhawan BN: Antithrombotic effect of curcumin. Thrombosis Research1985; 40(3): 413–417.
- Jordan W Cand Drew CR: Curcumin––a natural herb with anti-HIV activity. Journal of National Medical Association1996; 88(6): 333.
- Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL and Cole GM:Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study, Alzheimer’s Research & Therapy 2012;4(5):43.
- Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC and Hsieh CY: Phase I clinical trial of curcumin, a chemopreventiveagent, in patients with high-risk or pre-malignant lesions, Anticancer Researh2001; 21 (4B): 2895–2900.
- Milobedeska J, Kostanecki V and Lampe V: Structure of curcumin. Berichte der Deutschen Chemischen Gesellschaft 1910; 43:2163–2170.
- Lampe V and Milobedeska J. Studienuber curcumin. Berichte der Deutschen Chemischen Gesellschaft 1913; 46:2235–2240.
- Milobedzka J, Kostanecki SV and Lampe V: Chemishe Berichte1910, 43:2163-2170.
- Ruby AJ, Kuttan G, Babu KD, Rajasekharan KN and Kuttan R: Antitumor and oxidant activity of natural curcuminoids. Cancer Letters1995; 94:79-83.
- Rao TS, Basu N and Siddiqui HH: Anti-inflammatory activity of curcumin analogues. Indian Journal of Medical Research 1982; 75:574-578.
- Mukhopadhyay A, Basu N, Ghatak N andGujiral PK: Anti-inflammatory and irritant activities of curcumin analogues in rats. Agents and Actions 1982; 12:508-515.
- Ali M, Bagati A and Gupta J: Comparison of anti-inflammatory activity of curcumin analogs. Indian Drugs1995; 32:502-505.
- Ali M, Bagati A and Gupta J: Synthesis and anti-inflammatory activity of some curcumin analogs. Indian Journal of Chemistry, Organic Chemistry1995; 34B:884-888.
- Nurfina AN, Reksohadiprodjo MS, Timmerman H, Jenie UA, Sugiyanto D and Goot H: Synthesis of some symmetrical curcumin derivatives and their antiinflammatory activity. European Journal of Medicinal Chemistry1997; 32:321-328.
- Venkatesan P and Rao MNA: Structure-activity relationships for the inhibition of lipid peroxidation and the scavenging of free radicals by synthetic symmetrical curcumin analogues. Journal of Pharmacy and Pharmacology. 2000; 52: 1123–1128.
- Sreejayan N and Rao MNA: Free radical scavenging activity of curcuminoids. Arzneimittelforschung1996; 46: 169–171.
- Ahsan H, Parveen N, Khan NU and Hadi SM: Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chemico-Biological Interactions 1999; 121: 161–175.
- Osawa T, Sugiyama Y, Inayoshi M and Kawakishi S: Antioxidant activity of tetrahydrocurcuminoids. BiosciBiotechnolBiochem1995; 59:1609-1612.
- Sharma OP: Antioxidant activity of curcumin and related compounds. Biochemical Pharmacology1976; 25:1811-1812.
- Simon AD, P Allais, JL Duroux, Basly JP, Durand-Fontanier S and Delage C: Inhibitory effect of curcuminoids on MCF-7 cell proliferation and structure-activity relationships. Cancer Letters1998; 129: 111–116.
- Robinson TP, T Ehlers, IV RB, Bai X, Arbiser JL, Goldsmith DJ and Bowen JP: Design, synthesis and biological evaluation of angiogenesis inhibitors: aromatic enone and dienone analogues of curcumin. Bioorganic & Medicinal Chemistry Letters 2003; 13: 115–117.
- Lin L, Shi Q, Nyarko AK, Bastow KF, Wu CC, Su CY, Shih CY, Lee KH: Antitumor agents 250. Design and synthesis of new curcumin analogues as potential anti-prostate cancer agents. Journal of Medicinal Chemistry2006; 49:3963-3972.
- Soumyananda Chakraborti, Gopa Dhar, Vishnu Dwivedi, Amlan Das, Asim Poddar, Gopal Chakraborti, GautamBasu, Pinak Chakrabarti, Avadhesha Surolia, and Bhabatarak Bhattacharyya: Stable and Potent Analogues Derived from the Modification of the Dicarbonyl Moiety of Curcumin. Biochemistry2013; 52(42): 7449–7460.
- HidejiItokawa, Qian Shi, Toshiyuki Akiyama, Susan L, Morris-Natschkeand Kuo-Hsiung Lee: Chinese Medicine 2008; 3: 11.
- Artico M, Di Santo R, Costi R, Novellino G, Greco G, Massa S, Tramontano E, Marongiu ME, De Montis A and La Colla P: Geometrically and conformational lyrestrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling. Journal of Medicinal Chemistry1998; 41:3948-3960.
- Dikshit M, Rastogi L, Shukla R and Srimal RC: Prevention of ischaemia-induced biochemical changes by curcumin& quinidine in the cat heart. Indian Journal of Medical Research1995; 101: 31–35.
- Deodhar SD, Sethi R and Srimal RC: Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian Journal of Medical Research1980; 71, 632–634.
- Sharma OP: Antioxidant activity of curcumin and related compounds. Biochemical Pharmacology1976; 25(15): 1811–1812.
- Venugopal P Menon andAdluri Ram Sudheer: Antioxidant and Anti-inflammatory properties of curcumin; The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. Advances in Experimental Medicine and Biology 2007; 595: 105-125.
- Libby P: Inflammation in atherosclerosis. Nature 2002; 420(6917):868-874
- Coussens LM and Werb Z: Inflammation and cancer.Nature2002; 420(6917):860-867.
- Aggarwal B, Kumar A and Bharti A: Anticancer potential of curcumin: Preclinical and clinical studies. Anticancer Research 2003; 23(1A):363–398.
- Choi H, Chun Y, Kim S, Kim M and Park J: Curcumin inhibits hypoxiainduciblefactor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Molecular Pharmacology 2006; 70(5):1664–1671.
- Toshihiko Kawamori, Ronald Lubet, Vernon E. Steele, Gary J. Kelloff, Robert B. Kaskey, Chinthalapally V. Rao, and Bandaru S. Reddy: Chemopreventive Effect of Curcumin, a Naturally Occurring Anti-Inflammatory Agent, during the Promotion/Progression Stages of Colon Cancer. Cancer Research 1999; 59:597.
- Bar-Sela G, Epelbaum R and Schaffer M: Curcumin as an Anti-Cancer Agent: Review of the Gap between Basic and Clinical Applications; Current Medicinal Chemistry2010; 17(3): 190-197.
- Wongcharoen W and Phrommintikul A: The protective role of curcumin in cardiovascular diseases. International Journal of Cardiology 2009; 133(2):145-151.
- Chandran B andGoel A: A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytotherapy Research 2012; 26(11):1719-1725.
- Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA and Cole GM: Curcumin inhibits formation of amyloidbeta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. Journal of Biological Chemistry 2005; 280(7): 5892–5901.
- Shishir Shishodia, Gautam Sethi, and Bharat B Aggarwal: Curcumin: Getting Back to the Roots. Annals of New York Academy of Sciences 2005; 1056: 206–217.
- Osawa T: Nephroprotective and hepatoprotective effects of curcuminoids. Advances in Experimental Medicine and Biology 2007; 595:407-423.
- Shoba G, Joy D, Joseph T, Majeed M, Rajendran R andSrinivas PS: Influence of piperine on the pharmacokinetics of curcuminin animals and human volunteers. PlantaMedica1998; 64(4): 353–356.
- Wahlstrom B and Blennow G: A study on the fate of curcumininthe rat. Acta Pharmacologicaet Toxicologica (Copenhagen) 1978; 43(2): 86–92.
- Yang KY, Lin LC, Tseng TY, Wang SC and Tsai TH: Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. Journal of Chromatography B Analyte Technology & Biomedical Life Science2007;853(1–2): 183–189.
- Ravindranath V and Chandrasekhara N: Absorption and tissuedistribution of curcumin in rats. Toxicology 1980; 16(3): 259–265.
- Ravindranath V and Chandrasekhara N: Metabolism of curcumin–studies with [3H] curcumin. Toxicology 1981; 22(4): 337–344.
- Pan MH, Huang TM and Lin JK: Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metabolism and Disposition 1999; 27(4): 486–494.
- Garcea G, Berry DP, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA, Steward WP and Gescher AJ: Consumption of the putative chemopreventive agent curcuminbycancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiology Biomarkers & Prevention 2005; 14(1): 120–125.
- Garcea G, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA, Steward WP, Gescher AJ and Berry DP: Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. British Journal of Cancer 2004; 90(5): 1011–1015.
- Hoehle SI, Pfeiffer E, Solyom AM and Metzler M: Metabolism of curcuminoids in tissue slices and subcellular fractions fromrat liver. Journal of Agricultural and Food Chemistry2006; 54(3), 756–764.
- Holder GM, Plummer JL and Ryan AJ: The metabolism andexcretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. Xenobiotica1978; 8(12): 761–768.
- Asai A and Miyazawa T: Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sciences. 2000; 67(23): 2785–2793.
- Hoehle SI, Pfeiffer E and Metzler M: Glucuronidation of curcuminoids by human microsomal and recombinant UDP glucuronyltransferases. Molecular Nutrition& Food Research2007; 51(8): 932–938.
- Sharma R, Steward W and Gescher A. Pharmacokinetics and pharmacodynamics of curcumin. Advances in Experimental Medicine and Biology 2007; 595:453–470.
- Preetha Anand, Sherin G Thomas, Ajaikumar B. Kunnumakkara, Chitra Sundaram, Kuzhuvelil BHarikumar, Bokyung Sung, Sheeja TTharakan, Krishna Misra, Indira K Priyadarsini, Kallikat N Rajasekharan and Bharat B Aggarwal: Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochemical Pharmacology 2008; 76: 1590 – 1611.
- Anand P, Kunnumakkara AB, Newman RA and Aggarwal BB. Bioavailability of curcumin: problems and promises. Molecular Pharmacology 2007; 4:807–818.
- Benny Antony,Advanced Patent Search US7883728 B2, Arjuna Natural Extracts, Ltd.2013; (http://www.arjunanatural.com/HTML/biocurcumax.htm)
- YueA, Komiya T, Moteki H, Katsuzaki H, Imai K and Hibasami H:Selective induction of apoptosis by ar–turmerone isolated from turmeric(Curcuma longa)in two human leukemia cell lines but not in human stomach cancer cell lines.International Journal Molecular Medicine 2002; 9: 481-484.
- Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, Wexner SD and Giardiello FM: Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clinical Gastroenterology and Hepatology2006; 4(8): 1035–1038.
- Verma SP, Salamone E and Goldin B: Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides. Biochemical and Biophysical Research Communications 1997; 233(3): 692–696.
- Krishnakumar Illathu Madhavamenon, Abhilas Ravi, Dinesh Kumar and Balu Paulose Maliakel, M/S Akay Flavours& Aromatics Pvt Ltd, Formulation containing curcuminoids exhibiting enhanced bioavailability, US patent application,US20130029905A1,Jan31,2013.
- Karikar C, Maitra A, Bisht S, Feldmann G, Soni S and Ravi R: Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. Journal of Nanobiotechnology2007; 5: 3.
- Tiyaboonchai W, Tungpradit W and Plianbangchang P: Formulationand characterization of curcuminoids loaded solid lipid nanoparticles. International Journal of Pharmaceutics2007; 337(1–2): 299–306.
- Li L, Braiteh FS and Kurzrock R: Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 2005; 104(6): 1322–1331.
- Li L, Ahmed B, Mehta K and Kurzrock R: Liposomal curcumin with and without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer. Molecular Cancer Therapeutics 2007; 6(4): 1276–1282. Kunwar A, Barik A, Pandey R and Priyadarsini KI: Transport of liposomal and albumin loaded curcumin to living cells: an absorption and fluorescence spectroscopic study. Biochimicaet Biophysica Acta (BBA) General Subjects 2006; 1760(10): 1513-1520.
- Suresh D and Srinivasan K: Studies on the in vitro absorption of spice principles––Curcumin, capsaicin and piperine in rat intestines. Food and Chemical Toxicology 2007; 45(8): 1437-1442.
- Ma Z, Shayeganpour A, Brocks DR and Lavasanifar A, Samuel J: High-performance liquid chromatography analysis of curcumin in rat plasma: application to pharmacokinetics of polymeric micellar formulation of curcumin. Biomedical Chromatography 2007; 21(5): 546–552.
- Liu A, Lou H, Zhao L and Fan P: Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin. Journal of Pharmaceutical and Biomedical Analysis 2006; 40(3): 720–727.
- Letchford K, Liggins R and Burt H: Solubilization of hydrophobic drugs by methoxypoly(ethylene glycol)-block-polycaprolactonediblock copolymer micelles: Theoretical and experimental data and correlations. Journal of Pharmaceutical Sciences 2008; 97(3): 1179-1190.
- Vivek R. Yadav, Sahdeo Prasad, Ramaswamy Kannappan, Jayaraj Ravindran, Madan M. Chaturvedi, Lauri Vaahtera, Jaakko Parkkinen and Bharat B Aggarwal: Cyclodextrin-complexedcurcumin exhibits anti-inflammatory and antiproliferative activities superior to those of curcumin through higher cellular uptake; Biochemical Pharmacology 2010; 80: 1021–1032.
How to cite this article:
Elias G, Jacob PJ, Hareeshbabu E, Mathew VB, Krishnan B and Krishnakumar K: Curcumin: Transforming the Spice to a Wonder Drug. Int J Pharm Sci Res 2015; 6(7): 2671-81.doi: 10.13040/IJPSR.0975-8232.6(7).2671-80.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
G. Elias*, P. J. Jacob, E. Hareeshbabu, V. Baldwin Mathew, B. Krishnan and K. Krishnakumar
Department of Pharmaceutical Chemistry, St. James’ College of Pharmaceutical Sciences, Chalakudy, Kerala- 680307, India
12 November 2014
24 January, 2015
28 February, 2015
01 July, 2015