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Biological activities of curcumin and its analogues(Congeners) made by man and Mother Nature Preetha Anand Sherin G. Thomas Ajaikumar B. Kunnumakkara Chitra Sundaram Kuzhuvelil B. Harikumar Bokyung Sung Sheeja T. Tharakan Krishna Misra Indira K. Priyadarsini , Kallikat N. Rajasekharan , Bharat B. Aggarwal a Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, The University of Texas M.D. Anderson Cancer Center,1515 Holcombe Boulevard, Houston, TX 77030, USAb Department of Chemistry, University of Kerala, Thiruvananthapuram, Indiac Bio-informatics division, Indian Institute of Information Technology, Allahabad, Indiad Radiation and Photochemistry Division, Bhabha Atomic Research Centre, Mumbai-400085, India Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry Received 27 June 2008 powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; Accepted 7 August 2008 diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, andof liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain. Theutility of curcumin is limited by its color, lack of water solubility, and relatively low in vivo bioavailability. Because of the multiple therapeutic activities attributed to curcumin, how- ever, there is an intense search for a ‘‘super curcumin'' without these problems. Multiple Synthetic analogues approaches are being sought to overcome these limitations. These include discovery of natural curcumin analogues from turmeric; discovery of natural curcumin analogues made by Mother Nature; synthesis of ‘‘man-made'' curcumin analogues; reformulation of curcu- min with various oils and with inhibitors of metabolism (e.g., piperine); development ofliposomal and nanoparticle formulations of curcumin; conjugation of curcumin prodrugs;and linking curcumin with polyethylene glycol. Curcumin is a homodimer of feruloyl-methane containing a methoxy group and a hydroxyl group, a heptadiene with two Michaelacceptors, and an a,b-diketone. Structural homologues involving modification of all thesegroups are being considered. This review focuses on the status of all these approaches ingenerating a ‘‘super curcumin.''.
# 2008 Elsevier Inc. All rights reserved.
b-diketone that exhibits keto-enol tautomerism. Curcuminhas been shown to exhibit antioxidant, anti-inflammatory, Curcumin, commonly called diferuloyl methane, is a hydro- antimicrobial, and anticarcinogenic activities. It also has phobic polyphenol derived from the rhizome (turmeric) of the hepatoprotective and nephroprotective activities, suppresses herb Curcuma longa. Turmeric has been used traditionally for thrombosis, protects against myocardial infarction, and has many ailments because of its wide spectrum of pharmacolo- hypoglycemic and antirheumatic properties. Moreover, cur- gical activities. Curcumin has been identified as the active cumin has been shown in various animal models and human principle of turmeric; chemically, it is a bis-a, b-unsaturated studies to be extremely safe even at very high doses In * Corresponding author. Tel.: +1 713 7921817; fax: +1 713 7456339.
E-mail address: (B.B. Aggarwal).
0006-2952/$ – see front matter # 2008 Elsevier Inc. All rights reserved.
spite of its efficacy and safety, curcumin has not yet been has an E-configuration (trans C C bonds). The aryl rings may approved as a therapeutic agent. The poor aqueous solubility, be symmetrically or unsymmetrically substituted; the most relatively low bioavailability, and intense staining color of prevalent natural substituents are of the oxy type, such as curcumin have been highlighted as major problems; and hydroxy or methoxy elements. In this review, the curcumin consequently search for a ‘‘super curcumin'' without these analogues are classified in three groups: analogues from problems and with efficacy equal to or better than that of turmeric, analogues from Mother Nature, and synthetic curcumin is ongoing. This review presents the current status of the efforts toward finding this ‘‘super curcumin.'' The strategies used in the search for ‘‘super curcumin'' can Natural analogues from turmeric and its metabolites be categorized under two broad headings, namely (1) syntheticanalogues or derivatives and (2) formulations. The most The natural analogues of curcumin from turmeric and the explored of these two is the analogues and derivatives. The important metabolites of curcumin are depicted in The literature describes numerous synthetic curcumin analogues bioactivities of these analogues are summarized in with a wide range of applications. This review analyzes thecurcumin analogues with special reference to their biological Natural analogues from turmeric activity. The formulation part of this review describes the Turmeric contains three important analogues, curcumin, adjuvant, nanoparticle, liposomal and micellar delivery demethoxycurcumin (DMC), and bisdemethoxycurcumin systems, phospholipid complexes, prodrugs and PEGylation (BDMC). Collectively called curcuminoids, the three com- of curcumin.
pounds differ in methoxy substitution on the aromatic ring.
While curcumin has two symmetric o-methoxy phenols linkedthrough the a,b-unsaturated b-diketone moiety, BDMC, also Analogues and derivatives symmetric, is deficient in two o-methoxy substitutions, andDMC has an asymmetric structure with one of the phenyl rings Curcumin is a member of the linear diarylheptanoid class of having o-methoxy substitution. Of the three curcuminoids, natural products in which two oxy-substituted aryl moieties curcumin is the most abundant in turmeric, followed by DMC are linked together through a seven-carbon chain (The and BDMC. Commercially available curcumin mixture contain C7 chain of linear diarylheptanoids is known to have 77% curcumin, 17% DMC, and 3% BDMC.
unsaturation, oxo functions, enone moiety, and a 1,3-diketone A lesser known curcuminoid from turmeric is cyclocurcu- group. Except for the oxo and hydroxy functions, the C7 chain min, first isolated and characterized by Kiuchi et al. is generally unsubstituted. This unsaturation in the linker unit Structurally, cyclocurcumin differs from curcumin in the b- Fig. 1 – Natural analogues from turmeric and curcumin metabolites.
Table 1 – Activities of curcumin analogues derived from turmeric and of curcumin metabolites BDMC is more active than DMC or curcumin for cytotoxicity against ovarian cancer cells BDMC is less active than curcumin or DMC as an antioxidant and as an oxidative DNA cleaving agent BDMC is less active than curcumin or DMC as an inhibitor of peroxynitrite scavenger BDMC was most active when compared with DMC or curcumin for antimutagenic and anticarcinogenic activity BDMC is more active than curcumin or DMC for antitumor and antioxidant activity BDMC is more active than curcumin or DMC for suppression of carcinogenesis BDMC was more active than curcumin for reducing nicotine-induced oxidative stress BDMC improved innate immunity and transcription of MGAT-III and Toll-like receptors in AD pts BDMC is more active than curcumin for modulation of MDR1 gene BDMC is less active than curcumin or DMC in inhibiting singlet oxygen-induced DNA damage BDMC is less active than curcumin or DMC in binding and inhibiting Pgp and sensitizing cells to vinblastin BDMC is less active than curcumin or DMC in binding and inhibiting MRP1 and sensitizing cells to etoposide BDMC was more active than curcumin or DMC in protecting nerve and endothelial cells from beta amyloid-induced oxidative stress BDMC prevents DMH induced colon carcinogenesis BDMC is as active as curcumin in preventing DMH induced colon carcinogenesis BDMC is more active than curcumin in preventing alcohol and PUFA-induced oxidative stress BDMC is more active than curcumin in preventing CCL4-induced hepatotoxicity in rats BDMC is more active than curcumin in preventing alcohol and PUFA-induced cholesterol, TGs, PLs and FFA BDMC, curcumin, and DMC exhibit equivalent activity in suppression of blood glucose levels in diabetic mice through binding to PPAR-g BDMC is less active than curcumin and DMC in protecting rats from lead-induced neurotoxicity BDMC is less active than curcumin and DMC in suppressing NF-kB activation BDMC is more active than DMC or curcumin in inducing NRF2-mediated induction of heme oxygenase-1 BDMC is least active than DMC or curcumin in inducing p38 MAPK mediated induction of heme oxygenase-1 BDMC is least active than DMC or curcumin in inhibiting H2O2-induced lipid peroxidation and hemolysis of eythrocytes BDMC is least active than DMC or curcumin in inhibiting the proliferation of VSMC induced by ox-LDL and induction of LDL-R BDMC is least active than DMC or curcumin in inhibiting the liposomal peroxidation; and of COX1 and COX2 activity DMC is more potent than curcumin, BDMC and cyclocurcumin in inhibiting proliferation of breast cancer cells DMC is more potent than curcumin and BDMC in inducing nematocidal activity THC is less potent than curcumin in inhibiting the activity of 5-LOX; but more potent than curcumin in inhibiting COX-dependent arachidonic acid metabolism THC is more active than curcumin in preventing DMH-induced ACF formation in mice THC does not induces ROS production and membrane mobility coefficient but curcumin does THC is less active than curcumin in preventing PMA-induced skin tumor promotion in mice THC is more active than curcumin as an antioxidant THC is less active than curcumin as an antioxidant THC is less active under aerated condition than curcumin but under N2O purged conditions, THC is more active than curcumin in suppressing radiation-induced lipid peroxidation THCwas less active than curcumin, DMC or BDMC in suppressing NF-kB activation THC, HHC, OHC are less active than curcumin in suppressing NF-kB activation THC is more active than curcumin in suppressing nitrilotriacetate-induced oxidative renal damage THC is more active than curcumin in protecting from chloroquine-induced hepatotoxicity in rats THC is more active than curcumin in preventing brain lipid peroxidation in diabetic rats THC is more potent than curcumin for antioxidant and antidiabetic effects in rats THC is more potent than curcumin for modulation of renal and hepatic functional markers in diabetic rats THC is more potent than curcumin for modulation of blood glucose, plasma insulin and erythrocyte TBARS in diabetic rats THC is more potent than curcumin in decreasing blood glucose and increasing plasma insulin in diabetic rats THC is less potent than curcumin in modulation of ABC drug transporters THC's effect was comparable with curcumin on reduction of accummulation and cross-linking of collagen in diabetic rats THC exhibits stronger antioxidant activity than HHC OHC > curcumin > DMC > BDMC THC was more potent than curcumin in suppressing LDL oxidation THC is more active than curcumin in suppressing lipid peroxidation of erythrocyte membrane ghosts Cyclocur exhibits week anticancer activity Note: BDMC, bisdemethoxycurcumin; COX, cyclooxygenase; DMC, demethoxycurcumin; HHC, hexahydrocurcumin; LDL, low-densitylipoproteins; NF-kB, nuclear factor kappa B; OHC, octahydrocurcumin; ROS, reactive oxygen species; THC, tetrahydrocurcumin.
diketone link. In this molecule, the a,b-unsaturated b- Curcuma zedoaria, and Curcuma aromatica. Several research diketone moiety of curcumin is replaced by an a,b-unsatu- groups have investigated and compared their antioxidant, rated dihydropyranone moiety. To date, not many biological cardioprotective, neuroprotective, antidiabetic, antitumor, studies on cyclocurcumin have been reported; in one study, and chemopreventive activities, employing them either Simon et al. reported that this analogue was ineffective in individually or as mixtures. The curcuminoids have been inhibiting MCF-7 tumor cell proliferation and arrest of cell shown to be scavengers of free radicals and reactive oxygen cycle progression.
species (ROS), such as hydroxyl radicals, superoxide radicals, In the last few decades, efforts have been made to isolate singlet oxygen, peroxyl radicals, and peroxynitrite, whose curcuminoids from different sources, including Curcuma longa, production is implicated in the induction of oxidative stress They efficiently neutralized the stable free radical 1,1- most effective, DMC moderately effective, and BDMC the least diphenyl-2-picryl-hydrazyl (DPPH), and this reaction is often effective. Curcumin and DMC, but not BDMC, reduced Pb(II)- used in comparing the antioxidant activities of different induced memory deficits in rats. BDMC, on the other hand, compounds . Although all three are highly reactive in exhibited potent immunostimulatory effects and was able to these scavenging reactions, curcumin is more efficient than correct immune defects of Alzheimer's disease patients by DMC or BDMC.
enhancing phagocytosis of b-amyloid and regulation of the Curcuminoids exhibit differential antioxidant activity in transcription of b-1,4-mannosyl-glycoprotein 4-b-N-acetyl several in vitro and in vivo models. They inhibited lipid gluosaminyl transferase and toll-like receptors peroxidation in a variety of models such as rat brain Several in vitro and in vivo comparisons of the anti- homogenates, rat liver microsomeks, erythrocytes, liposomes, inflammatory and antitumor properties of curcuminoids have and macrophages, where peroxidation is induced by Fenton been reported. The activities varied depending on the type of reagent, as well as metals, H2O2, and 2,20-azo-bis(2-amidino- tumor and carcinogen employed. Curcumin, DMC, BDMC, and propane) hydrochloride (AAPH) They pre- a curcumin mix inhibited proliferation of a wide variety of vented singlet oxygen-stimulated DNA cleavage in plasmid tumor cells, including leukemia, lung cancer, head and neck pBR322 DNA , significantly reduced H2O2- and AAPH- cancer, pancreatic cancer, breast cancer, and prostate cancer induced hemolysis of erythrocytes and attenuated H2O2- Under identical experimental conditions, individual mediated endothelial cell viability . Curcuminoids were curcuminoids exhibited similar antiproliferative effects in able to inhibit cyclo-oxygenase (COX)-1 and (COX)-2 enzymes all these cell lines . In a separate study, however, DMC was and reduce AAPH-induced conjugated diene formation found to be more potent than curcumin or BDMC in inhibiting during linoleic acid oxidation In most of these actions, proliferation of MCF-7 breast cancer cells .
BDMC was less active than the other two, and curcumin was Curcuminoids show antimutagenic and anticarcinogenic the most potent of the three.
activity. They inhibited the mutagenic activity of 2-acetami- In a different in vivo study, BDMC was found to be more dofluorene and prevented crotean oil-induced skin tumor and effective than curcumin and DMC in increasing the life span of papilloma formation in mice . They significantly reduced Swiss albino mice bearing Ehrlich ascites and in reducing lipid tumor size in Swiss albino mice implanted with solid tumors peroxidation and superoxide generation in their macrophages Under identical treatment conditions, BDMC showed . Interestingly, curcuminoids could also act as pro- greater antitumor, antipromoter, and anticarcinogenic activ- oxidants. A report by Ahsan et al. compared pro-oxidant ities than curcumin or DMC. Similarly, in another study, the activities of the curcuminoids by measuring their abilities to cytotoxicity of BDMC against human ovarian cancer cell line enhance Cu(II)-induced cleavage of plasmid pBR322 DNA OVCAR-3 was more pronounced than that of curcumin or DMC through production of ROS. Of the three curcuminoids Curcumin and DMC had approximately the same potency examined, curcumin was more effective than DMC and BDMC in inhibiting 12-O-tetradecanoylphorbol-13-acetate (TPA)- in inducing DNA cleavage.
induced inflammation of mouse ears as well as TPA-induced Curcumin, DMC, and BDMC exhibit cardioprotective, transformation of cultured JB6 (P+) cells, while the activity of antidiabetic, and nematocidal activities. The three com- BDMC was less .
pounds inhibited proliferation of bovine vascular smooth P-glycoprotein (Pgp) is a member of the ATP-dependent muscle cells stimulated by oxidized low-density lipoproteins drug efflux protein pump (ABC transporter protein) super- (LDL) and delayed development of arteriosclerosis Again, family, linked to multidrug resistance (MDR) in cancer cells.
curcumin was the most efficient cardioprotective agent of the Curcumin, DMC, and BDMC had the ability to modulate the three. Turmeric extract containing the three curcuminoids function of Pgp in multidrug-resistant human cervical could cause lowering of the blood glucose level in type 2 carcinoma cell line KB-V1. The three curcuminoids were not diabetic KK-Ay mice, and its hypoglycemic effect improved effluxed by the Pgp transporter protein. At non-toxic doses, when administered in combination with sesquiterpenes .
the curcuminoids increased the sensitivity of cells to the It is the binding of curcuminoids to peroxisome proliferator- chemotherapeutic agent vinblastine. Of the three, curcumin ativated receptor-g (PPAR-g) and their acting as PPAR-g was the most effective in retaining the drug ; it also is an agonists that are responsible for their hypoglycemic effect.
effective MDR modulator The few and mild side effects The three curcuminoids individually did not show nemato- associated with curcuminoids make them attractive alter- cidal activity against Toxocara canis, but their nematocidal natives for better MDR modulation. Current research is activity increased remarkably when they were combined, investigating how these structurally related curcuminoids suggesting a synergistic action .
modulate antioxidant, anti-inflammatory, and antiprolifera- The neuroprotective effects of curcuminoids have been tive responses, with the principal aim of evaluating their investigated by various groups. Curcumin, DMC, and BDMC mechanisms of action.
protected PC12 rat pheochromocytoma and normal human Curcumin and DMC were more effective than BDMC in umbilical vein endothelial cells against b-amyloid-induced inducing p38 MAPK-mediated heme oxygenase-1 (HO-1) oxidative stress even better than a-tocopherol Curcumi- expression and activity in human endothelial cells . On noids have been found to be inhibitors of lead acetate (Pb(II))- the other hand, another related study reported that BDMC was induced neurotoxicity in primary hippocampal neurons .
more active than either curcumin or DMC in inducing NRF-2- They decreased lipid peroxidation, improved neuron viability, mediated induction of HO-1 and prevented decrease in glutathione levels in rat brain.
A recent study by Sandur et al. reported that curcumin, Under similar treatment concentrations, curcumin was the DMC, and BDMC exhibited differential abilities in regulation of anti-inflammatory and antiproliferative responses and ROS THC was ineffective in producing intracellular ROS in generation in chronic myeloid leukemia cell line KBM-5. Their human gingival fibroblasts, human submandibular gland relative potencies for suppression of tumor necrosis factor carcinoma cells , and KBM-5 cells . THC is less potent (TNF)-mediated nuclear factor-kB (NF-kB) activation are than curcumin in modulating ABC drug transporters . It curcumin > DMC > BDMC. Under similar experimental con- failed to inhibit TNF-induced NF-kB activation in KBM-5 and ditions, a mixture of curcuminoids showed better activity than RAW cells . THC is less active than the curcuminoids in any of the individual curcuminoids. However, the ROS- preventing TPA-induced tumor promotion in mouse skin and generating ability of curcuminoids in the same cells did not inflammation of mouse ears and less active than curcumin in correlate with either anti-inflammatory or antioxidant activ- preventing phorbol 12-myristate 13-acetate (PMA)-induced ity, and BDMC generated the highest quantities of ROS.
skin tumor promotion in mice On the other hand, THC Curcumin and DMC induced glutathione level to a similar was as effective as curcumin in inhibiting the release of extent, whereas BDMC was the least effective in inducing arachidionic acid and its metabolites, formation of prosta- glutathione, indicating that the anti-inflammatory and anti- glandin E2, and lipopolysaccharide (LPS)-induced COX-2 proliferative activities of curcuminoids are independent of expression in RAW cells . THC exhibited chemopreventive their redox-modulatory property.
activity by inhibiting 1,3-dimethylhydrazine-induced putativepreneoplastic aberrant crypt foci development in colons of Curcumin metabolites Various metabolites of curcumin have been reported, includ-ing dihydrocurcumin (DHC), tetrahydrocurcumin (THC), hex- ahydrocurcumin (HHC), octahydrocurcumin (OHC), curcumin Although curcumin, DMC, and BDMC differ in their chemical glucuronide, and curcumin sulfate (see ). THC, a partially structures only with regard to methoxy substitution, they reduced derivative of curcumin not found in turmeric, is one of exhibit significantly different antioxidant, antitumor, and the major metabolites of curcumin. Other reduced forms of anti-inflammatory activities. To date there has been no curcumin, HHC and OHC, have also been considered curcumin systematic study that clearly correlates the physicochemical metabolites, but have not been examined as extensively as and molecular properties of the three curcuminoids with their THC. THC is obtained by partial hydrogenation of curcumin; it biological activities. However, the existing literature provides is colorless and more hydrophilic than curcumin. THC exhibits some clues to understanding which group is actually greater antioxidant potential than curcumin in most models responsible for a given biological activity of the curcuminoids.
and presently is considered to be one of the factors responsible Since many reports suggest that curcumin has better for the in vivo antioxidant activity of curcumin (see radical scavenging and antioxidant ability than the other two, THC scavenged several free radicals, such as t-butoxyl and that DMC is superior to BDMC in this activity, the o- radicals, peroxyl radicals, and DPPH radical, better than the methoxy substitutions are certainly involved in this activity.
curcuminoids and was more effective in inhibiting AAPH- The hydrogen bonding interaction between the phenolic OH induced red blood cell hemolysis and lipid peroxidation in and the o-methoxy groups in curcumin markedly influences rabbit erythrocyte membrane ghosts and rat liver microsomes the O–H bond energy and H-atom abstraction by free radicals, The relative activities of THC and curcumin in thus making it a better free radical scavenger than BDMC inhibiting gamma radiation-induced lipid peroxidation in The ability of curcuminoids to act as antioxidants or pro- rat liver microsomes varied depending on the level of oxygen oxidants in the presence of metals such as Cu(II), Fe(II), or Pb(II) present THC is useful as a functional food factor because arises mainly from their chelating power . Although of its cardioprotective ability, which is even greater than that transition metal-chelation by curcumin can take place of curcumin . It inhibited oxidative modification of LDL and through either the diketone moiety or the o-methoxy phenol showed protective effects against oxidative stress in choles- moiety, in most cases chelation is observed only through the terol-fed rats The ability of THC to suppress nitrolotria- diketo group. Since the three curcuminoids possess similar cetate-induced oxidative renal damage was greater than that diketone moieties, their effects on metal-induced toxicity should be similar. The o-methoxy group may influence the Administration of THC to mice at an oral dose of 80 mg/kg electron density on the diketo group, however, which in turn body weight for nearly 15 days reduced hepatotoxicity induced can affect their chelating ability.
by the commonly used antibiotic erythromycin estolate and The a,b-unsaturated diketone moiety in the curcuminoids the antimalarial drug chloroquine At the same dose for is a Michael reaction acceptor, which belongs to the major nearly 45 days, THC showed an antihyperlipidemic effect in class of phase-II enzyme inducers Therefore, this streptozotocin–nicontinamide-induced oxidative stress in property may be responsible for inducing HO-1 and NF-kB diabetic rats The membrane-bound antioxidant suppression in cells by curcuminoids. Methoxy substitution enzymes, which were decreased in these mice, increased on the aromatic ring can significantly influence the interac- significantly on THC treatment. Oral administration of THC tions of curcuminoids with nucleophiles in the Michael also prevented changes in the levels of fatty acids, glucose, reaction. The reasons and the actual mechanism of the and insulin in the blood of diabetic rats . These studies antitumor activities of the curcuminoids are still far from reported that THC significantly decreased lipid peroxidation in understood. It is still not known why the o-methoxy-deficient different tissues of these rats. All these studies confirmed that BDMC is a more potent ROS inducer and the o-methoxy- THC, when compared with similar treatment doses of substituted curcumin is a more potent suppressor of NF-kB curcumin, had much greater antidiabetic effects.
activation The effect of change in the lipophilicity of the curcuminoids with methoxy substitution in influencing some the curcumin molecule, and a large number of synthetic of these activities also cannot be ignored.
analogues are known. The curcumin molecule is unique in its Hydrogenation of the heptadiene moiety in curcumin to physiological effects, however, having a greater number of produce THC markedly increased the antioxidant activity but molecular targets than any other molecule so far reported. In significantly reduced the antitumor and anti-inflammatory order to define a drug profile of this ‘‘wonder'' molecule, it is abilities. It is clear that the o-methoxy phenol groups, when necessary that, along with its synthetic analogues, its not linked through conjugation with the b-diketone moiety, naturally occurring analogues should be analyzed exhaus- make the molecule a better antioxidant. This lack of tively. shows a number of naturally occurring bioactive conjugation in THC also can cause C–C bond cleavage at the compounds having some structural similarity to the curcumin active methylene carbon of the b-diketone group during molecule, or at least having a pharmacophore containing one oxidation, yielding smaller o-methoxy phenol derivatives that aryl function with 3,4 substitution, i.e., either a methoxylated also act as antioxidants . Lack of NF-kB activity and ROS- phenol or catechol. These include ferulic acid, cinnamic acid, generating ability in THC clearly confirms that the a,b- caffeic acid, chlorogenic acid, capsaicin, gingerol, paradol unsaturated b-diketone moiety in conjugation with the zingerone, eugenol, dibenzoylmethane, dehydrozingerone, aromatic rings is definitely involved in these activities.
cassumuin and yakuchinone.
Although no comparative studies on the antioxidant Natural analogues made by Mother Nature potential of different naturally occurring analogues of curcu-min are available, a look at and indicates that an Structural variations in any lead compound are important for ortho-methoxylated phenolic chromophore is desirable its physiological activity, especially if these affect its receptor- , which may be present in a single aromatic ring (e.g., ferulic binding interactions. Structural variations also alter its acid, caffeic acid, chlorogenic acid, capsaicin, gingerols, pharmacokinetics, i.e., how easily the drug is absorbed, zingerone, eugenols) or in two aromatic rings (e.g., oregonin, distributed, metabolized, and excreted. Extensive structure- the potent nitric oxide synthase (iNOS) inhibitor, dehydro- activity relationship studies have been carried out on guairetic acid, yakuchinones, cassumunins). The same chro- Fig. 2 – Curcumin analogues from Mother Nature.
Table 2 – Relative potency of curcumin and its analogues made by Mother Nature Caffeic acid and ferulic acid but not cinnamic acid are more potent than curcumin in inhibiting lipid peroxidation Caffeic acid, ferulic acid, and chlorogenic acid are less potent than curcumin in inhibiting TPA-induced inflammation and promotion of Dibenzoylmethane is several times more potent (10-fold) than curcumin in inducing phase II enzymes, in inhibiting DMBA-induced mammary tumors in rodents and in inhibiting TPA-induced skin inflammation and tumor promotion 6-gingerol is more potent (107-fold) mutagen than curcumin whereas less potent in inhibiting TPA-induced inflammation, epidermal ornithine decarboxylase activity, and skin tumor promotion in mice Capsaicin is more potent than curcumin in lowering acidic glycoprotein and inflammation in arthritic rats Capsaicin and curcumin are more potent (1000-fold) than eugenol in inhibiting superoxide radical generation Capsaicin and curcumin are equally potent in inhibiting arachidonic acid metabolism Dehydrozingerone is less active than curcumin in inhibiting formation of conjugated dienes and spontaneous lipid peroxidation Dehydrozingerone is as active as curcumin but less active than isoeugenol in inhibiting Epstein–Barr virus antigen early antigen activation Yakuchinone A and B are as potent as curcumin in inhibiting LPS-induced nitric oxide production, TPA-induced superoxide production and lipid peroxidation Cassumunins A and B are more active than curcumin in protecting thymocytes from H2O2-induced toxicity Note: DMBA: 7,12-dimethylbenz[a]anthracene; H2O2, hydrogen peroxide; LPS, lipopolysachharide;TPA, 12-O-tetradecanoylphorbol-13-acetate.
mophore is responsible for both the antioxidant and pro- tural alteration on curcumin are shown in Scheme 1.
oxidant properties of curcumin and its analogues, which may Alterations of structure at all these molecular architectural be due to its radical-generating or hydrogen bond donor/ sites have been attempted. The modification of the basic structure of curcumin to access related compounds bychemical synthesis may be classified into three broad groups.
Synthetic analogues made by man These are termed ‘‘curcumin derivatives,'' ‘‘curcumin analo-gues,'' and ‘‘metal complexes of curcumin'' in this review.
Curcumin and its analogues have been the subject of Compounds that retain the basic structural features of computational studies, mostly with the intention of unravel- curcumin, such as the two dioxy-substituted benzene rings, ing its unique structural features and exploiting the informa- the –C C–CO–CH2–CO–C C-linker, and the oxy substituents tion for further molecular design. depicts the on the benzene rings, are designated as curcumin derivatives.
representative members of synthetic curcumin analogues The second group, the curcumin analogues, which encompass and summarizes the relative bioactivities of synthetic all other compounds with some perceived or claimed curcumin analogues. Recent high-level, ab initio, and compu- structural analogy to curcumin, now vastly outnumber the tationally intensive calculations have shown that the opti- first group. The members of the third group are metal mized structure of curcumin is planar and linear The complexes of curcumin and its analogues.
enol form has been found to be the stable ground state, and in The curcumin derivatives are generally synthesized by the optimized structure the methoxy groups are seen pointing derivatization, starting from curcumin. For example, the in the opposite direction with respect to the 1,3-keto-enol phenolic hydroxy group may be acylated, alkylated, glycosy- group, as shown in Scheme 1 This study showed that lated, and amino acylated (Scheme 2, the phenolic and enolic groups provide areas of high polarity The methoxy groups may be demethylated to hydroxy groups and the C7 bridge region is quite hydrophobic. Suggestions . The reactive methylene group of the linker may be based upon computational chemistry regarding redesign of acylated or alkylated or substituted by an arylidene group (Ar- curcumin to enhance its bioactivities have appeared in the CH ) , thereby introducing susbtituents on the C7 chain.
literature . In several recent studies that involve compu- A battery of molecular tinkering has been applied to tations of energy-minimized structures and subsequent curcumin with a view to preparing analogues. The more docking studies, only the b-diketo form has been investigated, common strategies are indicated in Scheme 3 (C). The so- despite the fact that curcumin exists mostly in the enol form.
called analogues of curcumin vary on a wide scale in their The single crystal X-ray diffraction studies on curcumin structural resemblance to curcumin, spanning a spectrum and its derivatives reported by several groups indicate the from structures such as (ferrocenyl-CH CH–CO)2 CH2 to enol form as the preferred tautomer. The crystal structure methyl ferulate.
studies show that curcumin in solid state has a perfectly The hydrogenation of the C7 linker double bonds and the delocalized central keto-enol unit coplanar with one trans-Ar- carbonyl groups affords the simplest of the analogues, such as CH CH-moiety. The plane of the second trans-CH CH-unit DHC, THC, HHC, and OHC, which are obtained by the reduction is twisted about 178 with respect to the former, planar, of curcumin (Scheme 4, D) .
Ar-CH CH-unit. This second unit is also not coplanar with Analogues that are sourced from curcumin also include its attached aryl unit. Thus the computationally derived those obtained by exploiting the reactivity of the central b- structure differs somewhat with that seen in the solid state diketone unit with hydrazine, its substituted derivatives, and hydroxylamine. Such heterocyclizations lead to bisstyrylpyr- The characteristic structural features of curcumin include azoles and isoxazoles in which the central 1,3-diketone ? 1,3- two o-methoxy phenol units, two enone moieties, and a 1,3- keto-enol system has been masked and rigidized (Scheme 5, diketone Ð 1,3-keto-enol system. The possibilities for struc- More recently, monosemicarbazone Table 3 – Relative activities of man-made curcumin analogues Diacetyl, diglycinoyl, diglycinoyl-di-piperoyl, dipiperoyl, and dialanoyl derivatives and curcumin-4,40-di-O-b-D glucopyranoside have more potent antibacterial and antifungal activities than curcumin Pyrazole analogues and a curcumin Knoevenagel condensate have more potent antimalarial, antioxidant and COX-1- and COX-2- inhibitory activities than curcumin Hydrazinocurcumin is a more potent inhibitor of endothelial cell proliferation than curcumin and it inhibits the cell cycle progression of colon cancer cells via antagonism of Ca2/CaM functions Semicarbazone of curcumin has greater antioxidant and antiproliferative activities but less antiradical activity than curcumin Compounds with ortho-diphenoxyl functionality exhibit greater antioxidant activity than curcumin Cinnamoyl derivatives are more active than curcumin in inhibiting p300 enzyme Symmetrical curcuminoids BJC005 and CHC002 have greater potency than curcumin in inhibiting Fos-Jun, tumor-induced angiogenesis, migration, and invasion Synthetic analogues with a modified aromatic ring and/or modified enone/dienone bridge between rings have more potent antiangiogenic and COX-1 inhibiting activity than curcumin Curcumin analogues that retain the 7-carbon spacer between the aryl rings, with a 5-carbon spacer and with a 3-carbon spacer, are more active than curcumin in inhibiting TPA-induced AP-1 and TNF-induced NF-kB activation and are more active antioxidantsthan curcumin Cyclic curcumin analogues have more potent cytostatic, antitumor and radical-scavenging activities than curcumin Synthesized EF24 and other related compounds have greater anticancer and antiangiogenic activities than curcumin Fused pyridine analogues of curcumin have more potent antioxidant activity than curcumin 2,6-dibenzylidenecyclohexanone, 2,5-dibenzylidenecyclopentanone, and 1,4-pentadiene-3-one substituted analogues of curcumin have more potent human cytochrome P450-inhibitory activity than curcumin Cinnamoyl derivatives of curcumin are more potent than curcumin in inhibiting HIV-1 integrase Mono-carbonyl analogues have the same or greater anti-inflammatory and antibacterial activity than curcumin Symmetrical analogues with aromatic rings having an alkoxy substitution are more potent in suppressing tumor growth than curcumin Aromatic enonic analogues are as or more potent than curcumin in inhibiting cell growth and proliferation Synthetic analogues with asymmetrical units such as a phenyl group with alkyl amide, chloro-substituted benzamide, or heteroaromatic amide moieties are more potent inhibitors of growth and tube formation than curcumin Symmetrical bis-alkynyl or alkyl pyridine and thiophene derivatives have more potent antiangiogenic activities than curcumin Curcumin–boron complexes are more potent than curcumin in inhibiting HIV-l and HIV-2 proteases Synthetic copper(II)-curcumin complexes have greater SOD mimicking, radiation-induced lipid peroxidation, and radical-scavenging activities than curcumin Manganese complexes of curcumin and diacetylcurcumin are more potent in preventing excitotoxicity and kainic acid-induced nitric oxide levels and neuronal cell damage in rats and are more potent nitric oxide radical scavengers and neuroprotectors than curcumin Copper(II) conjugate of a synthetic analogue with non-enolizable diketone is more potent than curcumin in inhibiting TNF-induced NF-kB activation and proliferation Cyclopalladated complexes of curcumin have more potent antiproliferative effects than curcumin Vanadium complex of curcumin has antidiabetic and hypolipidemic effects and improves the cardiovascular complications associated Vanadium, gallium, and indium complexes of curcumin and its derivatives have more potent cytotoxic activity than curcumin Curcumin derivatives with a modified aromatic ring and a cyclohexanone bridge between rings are more potent than curcumin in increasing mitochondrial membrane permeability Glycosylated derivatives of ciurcumin have more potent water-solubility and iron-chelating properties than curcumin BDMC-A is more active than curcumin in suppressing nicotine, alcohol and polyunsaturated fatty acid-induced oxidative stress, CCl4-induced hepatotoxicity and alcohol- and polyunsaturated fatty acid hyperlipidemia in rats Note: AP-1, activator protein-1; BDMC, bisdemethoxycurcumin;; BJC005, 1,7-bis(4-hydroxy-5-methoxy-3-nitrophenyl)-1,6-heptadiene-3,5-dione; Ca2/CaM, calcium 2+/calmodulin; CHC002, 1,7-bis(3,4,5-trimethoxyphenyl)-1,6-heptadiene-3,5-dione; COX, cyclooxygenase; EF24, 2,6-bis(2-fluorobenzylidene)piperidone; HIV, human immunodeficiency virus; NF-kB, nuclear factor kappa B; ROS, reactive oxygen species; SOD,superoxide dismutase; TNF, tumor necrosis.
, bisthiosemicarbazone and an ethylene diamine the C7 linker moiety (Scheme 7, adduct of curcumin have also appeared in the literature.
Most of the analogues of curcumin are not obtained from A further elaboration of this approach involves the use of b- curcumin but rather have been synthesized from smaller diketones other than acetylacetone derivatives. For example, synthons. Curcumins are usually assembled from aralde- the use of 2-acetylcycloalkanones has afforded analogues that hydes and acetylacetone, and this route enables synthesis of are conformation restricted. The C7 linker unit in these a diverse set of curcumin analogues starting from aralde- analogues now bears a cyclic structure (Scheme 8, hydes; a few typical examples are shown in Scheme 6 (F).
This assembly of curcuminoids from araldehydes and Yet another strategy has been alteration of the number of the acetylacetone has produced a large number of analogues.
carbons in the middle linker chain, resulting in analogues that The use of acetylacetone derivatives bearing substituents on are further removed from the native curcumin structure.
the central carbon further extends this route, leading to Reports show that deletion of one or both of the C C bonds analogues with alkyl substituents on the middle carbon of in the parent structure, omission of one C C and C O group
Fig. 3 – Curcumin analogues made by man. (A) Scheme 1: possible sites for structural modifications on curcumin; (B) Scheme2: curcumin derivatives; (C) Scheme 3: strategies for curcumin analogue preparation. (A) Modify –OMe and –OH groups;remove oxy groups; replace oxy groups. (B) Introduce/remove atoms/groups on aromatic rings; replace aromatic ring byhetero aromatic rings; or by multirings. (C) Alter number of –C C– and C O; incorporate –C C– in cyclic structure. (D)Replace 1,3-diketone by ketone; alter number of enone units; mask 1,3-diketone; convert 1,3-diketone to cyclic structures
Fig. 3. (Continued ).
like pyrazole or isoxazole. (D) Scheme 4: analogues synthesized by reduction of curcumin; (E) Scheme 5: analoguessynthesized by masking the central 3-diketone unit; (F) Scheme 6: typical examples of analogues from araldehydes; (G)Scheme 7: Typical examples of analogues from substituted acetylacetones; (H) Scheme 8: conformationally restrictedanalogues; (I) Scheme 9: C3 bridged analogues; (J) Scheme 10: C5 bridged analogues; (K) Scheme 11: C7, C9, C11, and longerbridged analogues. (L) Scheme 12: exotic analogues.
Fig. 3. (Continued ).
each (Scheme 9, I), avoidance of the –CH2–CO-unit (Scheme Antioxidant activity 10, J), or addition of two more C C bonds (Scheme 11, The antioxidant activities of curcumin and related compounds all have been attempted, leading to C3, C5, C9, C11 or have been investigated by a variety of assay systems, in both in longer linkers in addition to the natural C7 linker unit. A few vitro and in vivo conditions. The disparity in assay conditions randomly selected, nonprioritized, representative structures makes exact comparisons rather difficult. The general trends are shown in , as the total numbers of such analogues now that emerge are discussed in this section.
synthesized are too many to depict conveniently In one of the early papers on the antioxidant activity of curcumin and its derivatives, Sharma observed that the Incorporation of the shortened linker unit carbons in carbo- phenolic hydroxyl groups are needed for antioxidant activity cyclic rings has been attempted and that the presence of more than one of these groups, Analogues with only one-half of the basic curcumin as in the curcumin derivative bis(3,4-dihydroxycinnamoyl)- skeleton embedded in the structure also have been synthe- methane, confers better activity than that of curcumin itself sized. These include esters and amides of ferulic acid and . The mechanistic aspects of curcumin antioxidant activity other similar cinnamic acids Further structural have been more recently investigated at length, and the recent alterations based on exotic modifications and more drastic studies by Wright Sun et al. , Priyadarsini et al. molecular surgery of curcumin appear in the literature Ligeret et al. , Suzuki et al. , and Chen et al. seem to suggest that the phenolic OH groups are important in the Several metal complexes of curcumin, derivatives of antioxidant activity, as was earlier surmised by Barclay et al.
curcumin, and analogues of curcumin have been reported.
and Venkatesan and Rao A possible role for the b- These have generally been obtained by the reaction of diketone moiety was suggested by Sugiyama et al. based curcumin or one of its analogues with a metal salt. Boron on their observations using dimethyltetrahydrocurcumin and has long been known to form a complex with curcumin .
further advocated by the work of Jovanovic et al.
The complex resulting from combination of a molecule of The presence of an ortho alkoxy group seems to potentiate curcumin, oxalic acid, and a boron atom, sourced from boric the antioxidant activity as does an additional hydroxy oxide or acid, is known as rubrocurcumin. The complexation group as in bis(3,4-dihydroxy)cinnamoylmethane . The of two curcumin molecules with a boron atom affords effect of the position of the hydroxy group has been investigated rosocyanin. Complexes of copper , iron, manga- under in vivo conditions and it seems that the 2- nese , palladium vanadyl gallium, and hydroxyphenyl group, as seen in bis(2-hydroxycinnmoyl)- indium have been reported.
methane, yields better antioxidant activity than the 4-hydro- xyphenyl group, as present in curcumin. The reduction of the nyl]benzoate dimethyl ester, were more potent COX-1 C C bonds of the C7 linker leading to THC is apparently not inhibitors than curcumin. Even the presence of the b-diketone deleterious to antioxidant activity . Telomere repeat moiety per se was not a must; its replacement by a pyrazole or amplification protocol assays have shown that, though phe- isoxazole unit did not abolish the COX-inhibitory activity of nolic hydroxy groups are desirable, the enone and b-diketone curcumin. Further, the pyrazole replacement provides better moieties are not unavoidable . The desirability of the b- COX-1/COX-2 selectivity The architectural change of the diketo unit has been studied by Sardijiman et al. using ‘‘ene-[1,3-dioxo]-ene'' C7 linker in curcumin to a C5 ‘‘ene-oxo- ene,'' as in 1,4-pentadiene-3-ones and their cyclopenta- and hexanones, and cyclopentanones having a C5 linker. These cyclohexa-analogues, has been reported to improve the inhibi- workers report that the 4-hydroxyphenyl group confers potent tion of LPS-induced TNF-a and interleukin-6 expression .
antioxidant activity, which is much enhanced by one, or two,methoxy susbstituents ortho to the hydroxy group. These C5- Anticancer and anticarcinogenic activity The anticarcinogenic properties of classical Michael acceptors, greater antioxidant activity than curcumin. In a similar recognized by Talalay et al. , have been demonstrated in observation among 2,6-bis-benzylidenepiperidones, cyclohep- curcumin and it has been suggested that the presence of a tanones and acetones, Youssef et al. demonstrated greater hydroxyphenyl group in compounds analogous to curcumin, antioxidant activity in those examples that bear a 3-alkoxy-4- especially in the 2-position, is supportive of the chemopro- hydroxyphenyl unit The enhancement of antioxidant tective activity through the ability to induce Phase II activity offered by additional hydroxy substituents on the detoxification enzymes. The necessity of the ‘‘ene-[1,3- phenyl rings of curcumin-type compounds has been further dioxo]-ene'' C7 linker, however, could not be firmly estab- demonstrated by Venkateswarlu et al.
lished; Dinkova-Kostova et al. observed activity in dibenzoyl The antioxidant potential of curcumin complexes has been and di(2-hydroxybenzoyl)methanes, which are not examples investigated by another approach. The manganese complexes of classic Michael acceptors. An early report by Markaverich of curcumin and its diacetyl derivative were found to show et al. suggests that the Michael acceptor type 2,6-bis(3,4- greater superoxide dismutase (SOD) activity HO radical- scavenging activity and nitric oxide radical-scavenging nones, having only a ‘‘ene-oxo-ene'' motif, could inhibit activity than the parent molecules. The copper complex cancer cell proliferation in vitro and in vivo. Dinkova-Kostova of curcumin also has been found to exhibit antioxidant, et al. investigated a large set of Michael acceptors and superoxide-scavenging, and SOD enzyme-mimicking activ- concluded that the shortened C5 ‘‘ene-oxo-ene'' version, as ities superior to those of curcumin itself . In an present in 2,6-bis(2 hydroxybenzylidene)cyclopentanone as a investigation based on the trolox-equivalent antioxidant typical example, is sufficient to confer potent quinone capacity assay, Mohammadi et al. found that the vandyl, reductase inducer activity, and the presence of a 2-hydro- indium, and gallium complexes of curcumin I and curcumin III xyphenyl unit in the bisbenzylidenealkanones and biscy- were more potent than the respective ligands. In summary, cloalkanones profoundly increases inducer potency. In a study antioxidant activity seems to require, minimally, two hydro- of the inhibition of formation of the Fos-Jun-DNA complex, the xyphenyl units connected together through a linker unit, and presence of a 4-hydroxyphenyl, flanked by an adjacent the activity increases with additional oxy groups, especially if methoxy or nitro group on the phenyl ring in curcumin these are adjacent to one another. Whether the linker unit analogues, conferred better potency . Interestingly, the 4- should contain an unsaturation and/or an oxo group has not nitrophenyl analogue also was active. It is tempting to been conclusively established yet.
speculate that the ability of the phenyl ring substituent toaccept hydrogen bonds, either intramolecularly or intermo- lecularly, is a structural factor possibly leading to bioactivity.
Saturation of the alkene and reduction of the carbonyl In a study encompassing a large collection of curcumin functions in the C7 linker of curcumin appear to reduce its analogues of diverse structural types, Ishida et al. anti-inflammatory activity by suppressing activation of NF-kB observed that diarylheptanoids of curcumin type with 3,4- through inhibition of IkB kinase activity . An early study dihydroxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, and pointed to the fact that the hydroxyphenyl unit in curcumin the pyrazole analogue of curcumin-I were cytotoxic, whereas confers anti-inflammatory activity since acylation and alkyla- the reduced curcumin types were inactive. These workers also tion of the phenolic hydroxy group of curcumin were found to examined a panel of 1,3-diarylpropan-1,3-diones that are drastically reduce its anti-inflammatory activity Nurfina examples of the C3 linker type, and the most active compound et al. suggested that the presence of a 4-hydroxyphenyl unit is happens to be a –CO–CHBr–CO– derivative whose structure, by required for anti-inflammatory activity and that this activity virtue of the very reactive bromo substituent, is quite remote seems to increase if additional small-sized alkyl or methoxy from that of curcumin. Other work done in the same groups are present on the adjacent 3- and 5-positions on the laboratories showed that bis(3,4-dimethoxyphenyl) units phenyl ring Hong et al. found that the phenolic and the ‘‘ene-[1,3-dioxo]-ene'' segment in curcumin analogues hydroxyl groups are required for inhibition of COX-1 activity.
are important structural factors that confer antiandrogenic However, Handler et al. recently observed that many activity, with possible application in prostate cancer therapy analogues of curcumin that lack a 4-hydroxyphenyl unit, such The observation of Shim et al. that the so-called hydrazinocurcumin analogues, which are formulated more correctly as 3,5-bisstyrylpyrazoles, are more antiangiogenic than curcumin also seems to point to the importance of the seems to be desirable. The recent report by Ohori et al. 1,3-diketo unit or its masked version as a pyrazole or isoxazole seems to support this very general surmise. The presence of a moiety. Extension of this work to more curcumin analogues halo substituent such as F does not provide much enhance- has been reported by Ohtsu et al. who found that the ment, the case of EF24 being a very successful exception.
presence of a methoxyphenyl or fluorophenyl and introduc-tion of a CH2CH2COOEt group into the 1,3-diketo unit affords anovel set of curcuminoid-type antiandrogens. More recently, Dutta et al. showed that the monosemicarbazone ofcurcumin has greater cytotoxic activity than curcumin itself.
Apart from the synthetic analogues, several other strategies In one of the more significant findings on the anticancer have been evaluated to enhance the biological activity of activity of compounds inspired by curcumin, Adams et al.
curcumin. These strategies include adjuvants, nanoparticles, announced the superior activity of 2,6-bis(2-fluor- liposomes, micelles, and phospholipid complexes. The adju- obenzylidene)piperidone (EF24) in antiangiogenesis, cell cycle vants were selected on the basis of their ability to prevent the arrest, and apoptosis of cancer cells. These authors observed rapid metabolism of curcumin by interfering with the that the bis-benzylidenepiperidone, pyrone, and cyclohex- enzymes that catalyze the metabolism of curcumin. All other anone derivatives, containing the a,b-unsaturated ketone formulations mentioned are designed primarily to increase unit, exhibit much greater anticancer and antiangiogenesis absorption of curcumin into tissues. Nanoparticles can activities than curcumin, with its 1, 3-diketone unit. They also provide more penetration to membrane barriers because of observed that hydroxyl susbtituent in position 2 generally their small size. Besides their size, their potential for confers good activity, and concluded that incorporation of the modification for targeting specific organs makes them a,b-unsaturated keto group into a heteroatom-containing ring excellent drug carriers. Liposomes, micelles, and phospholipid was desirable. The improved cytotoxicity of bis-(3-alkoxy-4- complexes can reduce the hydrophobicity of curcumin; these hydroxybenzylidene) piperidones has been reported by Yous- carriers also can increase the permeability of membrane sef and El-Sherbeny . In this connection, it is notable that barriers by interacting with the membrane components.
the increased cytotoxicity provided by more than one Recently it was also reported that the water solubility of hydroxyl substituent on the phenyl ring of curcuminoids is curcumin could be 12-fold by the use of heat .
further exemplified by the analogues reported by Venkates-warlu et al.
The question of the essentiality of the b-keto unit in the bioactivity of curcuminoids has been addressed recently by Piperine is known to inhibit hepatic and intestinal glucur- Lin et al. Their work seems to suggest that the enol- onidation. When combined with piperine, the elimination keto moiety is responsible for the antiandrogenic activity and half-life and clearance of curcumin were significantly that the di-keto form probably is not an active form. In an decreased, resulting in an increase of bioavailability to 154% ambitious study, Weber et al. investigated the inhibition of that of curcumin alone in rats. In contrast, the increase in TNF-a-induced activation of NF-kB by a large collection of bioavailability was 2000% in humans, clearly showing that the curcumin analogues, including those with C7, C5, or C3 linkers effect of piperine on bioavailability of curcumin is much between the aromatic rings. They observed that activity did greater in humans than in rats. A human volunteer trial not depend on linker length, except that compounds with the conducted by our group revealed the enhancing effect of a,b-unsaturated keto unit were more generally active, 1,5- piperine on serum curcumin level. Six healthy adult male bis(3-pyridyl)-1,4-pentadien-3-one being the most active human volunteers took 2 g of curcumin with or without 5 mg among the 72 compounds tested. Those without the enone piperine (as Bioperine1) in this cross-over design study. Three unit also exhibited activity, however, and the inhibitory subjects were randomized to receive curcumin only, while the activity of the activation of NF-kB did not correlate with the remaining three received the curcumin + piperine combina- antioxidant activity of the compounds tested. Many of the tion. One week following initial drug administration, volun- active compounds bore hydroxyl and/or methoxyphenyl teers were crossed over to the other therapy and blood groups, including the simple 4-hydroxy-3-methoxybenzala- samples were obtained for evaluation. The presence of ceophenone. Extending their search for a compound with better piperine was found to double the absorption of curcumin antiandrogen activity, Lin et al. examined a set of 50 The effect of piperine on tissue uptake of a radiolabeled curcumin analogues, encompassing monophenyl and hetero- fluoropropyl-substituted curcumin was evaluated in mice.
aryl curcumin analogues, curcumin analogues diversely sub- Mice that received piperine had 48% greater brain uptake of stituted on the phenyl rings, and curcumin analogues with curcumin after 2 min than mice that did not receive piperine.
various linkers. Most of the active compounds had methoxy However, the uptake in other organs was not found to be substituents and several were C7 curcumin analogues with a significantly improved by piperine in this study; the authors substituted methylene carbon of the 1,3-diketo moiety.
think this observation can be explained by the poor solubility Overall, it seems that shortening of the C7 linker to a C5 of piperine in 10% ethanolic saline (injection medium) linker results in compounds that are more active than Some other agents that showed a synergistic effect when curcumin, with the caveat that the substituent groups and used in combination with curcumin in various in vitro studies their distribution pattern on the phenyl ring should be kept in look promising for further evaluation. Five patients with view. Alkoxy and hydroxy substituents are, in general, activity familial adenomatous polyposis who had undergone colect- promoting, and the presence of unsaturation and an oxo group omy received curcumin 480 mg and quercetin 20 mg orally 3 times a day. The number and size of polyps were assessed at that containing free curcuminoids . Sou et al. very baseline and after therapy. All five patients had decreases in recently reported that lipid-based nanoparticles provide polyp number and size, 60.4% and 50.9%, respectively, from improved intravenous delivery of curcumin to tissue macro- baseline after a mean of 6 months of this treatment.
phages. At 6 h after intravenous injection in rats via the tail Though the authors did not compare the effects of this vein, curcumin in a nanoparticle delivery system was combination treatment with those of the single agents, massively distributed in macrophages of the bone marrow this study at least throws light on the therapeutic value of and spleen. Overall, nanoparticle-based systems for curcu- this combination .
min delivery are still in their infancy, and much progress is The synergistic inhibitory effect of curcumin and genistein expected in this area.
against pesticide-induced growth of estrogen-dependentMCF-7 breast carcinoma cells has been reported. It was Liposomes, micelles, and other delivery systems showed that a combination of curcumin and genisteincompletely inhibited the cellular proliferation induced by an Liposomes are excellent drug delivery systems since they individual pesticide or a mixture of pesticides, and that the can carry both hydrophilic and hydrophobic molecules. The inhibitory effect was superior to the individual effects of either in vitro and in vivo antitumor activity of liposomal curcumin curcumin or genistein. Curcumin uptake within rat skin after against human pancreatic carcinoma cells was evaluated topical application of a curcumin hydrogel, with or without and demonstrated that liposomal curcumin not only eugenol or terpeneol pretreatment, was evaluated in an in vivo inhibited pancreatic carcinoma growth but also exhibited study. The effects of eugenol and terpeneol as enhancers of antiangiogenic effects. Liposomal curcumin suppressed skin curcumin absorption were demonstrated; 8 h after pancreatic carcinoma growth in murine xenograft models application, curcumin levels in skin were 2.2- and 2.5-fold and inhibited tumor angiogenesis. In the in vivo part of this greater, respectively, in mice that received eugenol or study, the effect of liposomal curcumin was evaluated in terpeniol pretreatment than in mice that received curcumin comparison to no treatment or to treatment with a alone. These observations indicate that these absorption- liposomal vehicle in mice. Comparison of the effects of enhancing agents may also be effective as adjuvants. Epigallo- liposomal curcumin with those of free curcumin and catechin-3-gallate, a component of green tea, could counteract biodistribution profiles of liposomal curcumin and free certain activities attributed to curcumin. BCM-95 (also called curcumin have yet to be reported.
Biocurcumax) curcuminoids combined with turmeric oil The preclinical anticancer activity of a liposomal curcu- (turmerons) in a specific proportion enhanced the bioavail- min formulation in colorectal cancer was recently evaluated.
ability and showed better absorption into blood and had longer This study also compared the efficacy of liposomal curcumin retention time than curcumin alone. Currently a multicenter, with that of oxaliplatin, a standard chemotherapeutic agent phase II, randomized, double-blinded, placebo-controlled clin- for colorectal cancer. There was synergism between liposo- ical study is ongoing to assess the efficacy and safety of BCM-95 mal curcumin and oxaliplatin at a ratio of 4:1 in LoVo cells in in oral premalignant lesions or cervical cancer vitro. In vivo, significant tumor growth inhibition wasobserved in Colo205 and LoVo xenografts, and the growth inhibition by liposomal curcumin was greater than that byoxaliplatin in Colo205 cells. This study established that Targeted and triggered drug delivery systems employing liposomal curcumin has comparable or greater growth- nanoparticle technology have emerged as solutions to the inhibitory and apoptotic effects than oxaliplatin in colorectal problems of enhancing the bioavailability of therapeutic cancer both in vitro and in vivo. This group is currently agents and reducing their unwanted side effects. The developing liposomal curcumin for introduction into the synthesis, physicochemical characterization, and cancer- clinical setting .
related applications of a polymer-based nanoparticle of Ruby et al. reported the antitumor and antioxidant curcumin named ‘‘nanocurcumin'' was reported recently.
activities of neutral unilamellar liposomal curcuminoids in Nanocurcumin was found to have in vitro activity similar to mice. The in vitro cellular uptake studies of liposomal and that of free curcumin in pancreatic cancer cell lines, albumin-loaded curcumin showed that liposomal vehicle is inhibiting activation of the transcription factor NF-kB and capable of loading more curcumin into cells than either reducing steady-state levels of pro-inflammatory cytokines human serum albumin or aqueous dimethyl sulfoxide, and such as interleukins and TNF-a. The authors determined lymphoma cells showed greater uptake of curcumin than neither the in vivo effect of nanocurcumin in mice nor its lymphocytes. Nevertheless, in vivo preclinical studies are biodistribution, which would show any potential increase of warranted to verify that liposomal curcumin has greater in vivo efficacy of nanocurcumin over that of free curcumin.
bioavailability and efficacy than free curcumin. A 13 105-fold Curcuminoid-loaded solid lipid nanoparticles for topical greater solubility of curcumin in a polymeric micellar application were found to be stable for 6 months at room temperature and gave prolonged in vitro release of curcumi- block-polycaprolactone diblock copolymers (MePEG-b-PCL) noids for up to 12 h. Furthermore, the light and oxygen was also reported indicating the possibility of further sensitivities of curcuminoids were strongly reduced by their exploration on this micellar formulation incorporation into this unique type of formulation. An in vivo Another study compared the phototoxic effects of curcu- study revealed the improved efficiency of this topical cream min formulations in cyclodextrin and liposomes. Liposomes containing curcuminoid-loaded solid lipid nanoparticles over were proved to be a more suitable curcumin carrier system, since as much as 30% of the phototoxic effect caused by Curcumin–phospholipid complex significantly protected the curcumin in cyclodextrin was obtained with about 1/30 of the liver from carbon tetrachloride-induced acute liver damage curcumin concentration in liposomes. Furthermore, curcumin in rats by restoring levels of the enzymes of the liver prepared in cyclodextrin yielded a significantly greater rate of glutathione system and of SOD, catalase, and thiobarbituric cell death than curcumin alone acid reactive substances. Yet another study explored The intestinal absorption of curcumin and a micellar whether formulation with phosphatidylcholine increases curcumin formulation with phospholipid and a bile salt was the oral bioavailability or affects the metabolite profile of evaluated using an in vitro model consisting of everted rat curcumin in vivo. Male Wistar rats received 340 mg/kg of intestinal sacs. This study suggested that curcumin is either unformulated curcumin or curcumin formulated with biologically transformed during absorption. Further, the in phosphatidylcholine (Meriva) by oral gavage. Curcumin, the vitro intestinal absorption of curcumin was found to increase accompanying curcuminoids desmethoxycurcumin and bis- from 47% to 56% when it was prepared in micelles.
desmethoxycurcumin, and the metabolites THC, HHC, Pharmacokinetic studies demonstrated that curcumin in a curcumin glucuronide, and curcumin sulfate were identified polymeric micellar formulation had a 60-fold higher biological in plasma, intestinal mucosa, and liver of rats that had half-life in rats than curcumin solubilized in a mixture of received Meriva. Peak plasma levels for parent curcumin dimethylacetamide, polyethylene glycol (PEG), and dextrose after administration of Meriva were fivefold higher than those after administration of unformulated curcumin.
Monoesters of curcumin with valine and glycine and Similarly, liver levels of curcumin were higher after diesters with valine, glutamic acid, and demethylenated administration of Meriva than after administration of piperic acid have been prepared and assessed for their unformulated curcumin. In contrast, curcumin concentra- antimicrobial and anticancer activities. The results of this tions in the gastrointestinal mucosa after ingestion of study suggested that diesters of curcumin are relatively more Meriva were somewhat lower than those observed after active than curcumin itself because of their increased administration of unformulated curcumin. These results solubility, slow metabolism, and better cellular uptake.
suggest that curcumin formulated with phosphatidylcho- Moreover, monoesters of curcumin had better antimicrobial line furnishes higher systemic levels of the parent agent activity than their corresponding diesters, indicating the than unformulated curcumin .
significant role of a free phenolic group .
In an attempt to reduce the color staining effect and Curcumin prodrugs enhance the stability of curcumin, which are its principallimitations in dermatological applications, the curcumin was Two curcumin prodrugs, N-maleoyl-L-valine-curcumin and N- microencapsulated in gelatin. The results of this study maleoyl-glycine-curcumin, were synthesized and evaluated revealed that microencapsulation resolved the color-staining for the selective inhibition of growth of bladder cancer cell problem and enhanced the flow properties and photostability lines. This study revealed that activation of curcumin of curcumin .
prodrugs via hydrolysis functions of cellular esterase could Gal et al. demonstrated the antioxidant effect of inhibit the growth of tumor cells and reduce the side effects of liposomal curcumin against copper-induced lipid peroxida- these drugs on normal diploid cells .
tion. Very recently, the feasibility of a curcumin microemul- A DNA-curcumin-tetraglycine was prepared by a deoxy sion containing ethyl oleate, lecithin, and Tween80 as an 11-mer oligonucleotide, 50-GTTAGGGTTAG-30, complemen- ultrasonic drug delivery carrier was evaluated Further- tary to a repeat sequence of human telomerase RNA more, Thangapazham et al. reported that a liposomal template and linked through phosphate and a C-2 linker curcumin formulation had 10-fold higher antiproliferative to a bioactive tetraglycine conjugate of curcumin. This activity in human prostate cancer cell lines than free molecule, targeted by an antisense mechanism to telomer- ase, has been found to act as a prodrug affecting cell growth.
Phospholipid complexes In a study, curcumin (100 mg/kg) or curcumin–phospholipidcomplex (corresponding to 100 mg/kg curcumin) was admi- PEGylation is used mainly to increase the solubility and nistered orally to rats. Curcumin–phospholipid complex decrease the degradation of drug molecules. The aqueous produced a maximum plasma curcumin level of 600 ng/ml solubility of curcumin was increased by formulating it with 2.33 h after oral administration, while free curcumin yielded MePEG-b-PCL . A recent study by Salmaso et al. a maximum plasma concentration of 267 ng/ml 1.62 h after reported significant increase in solubility of curcumin in a oral administration. The curcumin–phospholipid complex bioconjugate with PEG and cyclodextrin. A bioconjugate with yielded a curcumin half-life about 1.5-fold greater than that beta-cyclodextrin and PEG was prepared and folic acid was yielded by free curcumin. These results indicate that a incorporated for targeting purposes. This bioconjugate, CD- curcumin–phospholipid complex can significantly increase (C6-PEG)5-FA, formed a complex with curcumin and increased circulating levels of presumably active curcumin in rats.
curcumin solubility by about 3200-fold as compared to Another study showed that a curcumin–phospholipid native beta-cyclodextrins; this bioconjugation reduced the complex yielded a threefold greater aqueous solubility degradation rates of curcumin at pH 6.5 and 7.2 by 10- and 45- and a better hepatoprotective effect than free curcumin.
fold, respectively. In vitro studies using folic acid receptor- overexpressing and -non-expressing cells demonstrated that unravel curcumin analogues that would be more suitable for the new carrier possesses potential selectivity for the folic acid human clinical trials.
receptor-overexpressing tumor cells. Two conjugates ofcurcumin with PEGs of different molecular weights exhibitedgreater cytotoxicity than unconjugated curcumin .
Although not meant to evaluate the effect of PEGylation,researchers used a PEG derivative to make nanocurcumin, Dr. Aggarwal is the Ransom Horne, Jr., Professor of Cancer which is described in section D2 of this review.
Research. This work was supported by grants from the ClaytonFoundation for Research. The authors thank Ms. Kathryn Halefor carefully reviewing this manuscript.
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Mem. S.A.It. Suppl. Vol. 8, 64 Two platform independent versions of ATLAS12 Institut f¨ur Astronomie, Universit¨at Wien, T¨urkenschanzstraße 17, 1180 Vienna, Austriae-mail: [email protected] Abstract. ATLAS12 makes use of some non-standard features of the VAX/VMS compiler,which is highly appreciable if one uses a VMS workstation, but causes problems of portabil-ity that make it difficult to compile ATLAS12 on various non-VMS operating systems. Thisarticle describes the modifications to ATLAS12 that became necessary in order to get thiscode running with the open source GNU compiler (g77), which is easily available on mostLinux/Unix based systems (including Mac OS X). We also present our parallel and modu-larised Ada95 version of ATLAS12 and give an overview of CAMAS, our new magneticstellar atmosphere code.