curcumin and methyl-3-methoxy-4-hydroxystyryl-ketone

Natural products serve as a key source for the design, discovery and development of potentially novel drug like candidates for life threatening diseases. Curcumin is one such medicinally important molecule reported for an array of biological activities. However, it has major drawbacks of very poor bioavailability and solubility. Alternatively, structural analogs and degradants of curcumin have been investigated, which have emerged as promising scaffolds with diverse biological activities. Dehydrozingerone (DZG) also known as feruloylmethane, is one such recognized degradant which is a half structural analog of curcumin. It exists as a natural phenolic compound obtained from rhizomes of Zingiber officinale, which has attracted much attention of medicinal chemists. DZG is known to have a broad range of biological activities like antioxidant, anticancer, anti-inflammatory, anti-depressant, anti-malarial, antifungal, anti-platelet and many others. DZG has also been studied in resolving issues pertaining to curcumin since it shares many structural similarities with curcumin. Considering this, in the present review we have put forward an effort to revise and systematically discuss the research involving DZG with its biological diversity. From literature, it is quite clear that DZG and its structural analogs have exhibited significant potential in facilitating design and development of novel medicinally active lead compounds with improved metabolic and pharmacokinetic profiles.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Antifungal Agents; Antimalarials; Antineoplastic Agents, Phytogenic; Antioxidants; Curcumin; Drug Design; Humans; Molecular Structure; Platelet Aggregation Inhibitors; Styrenes; Zingiber officinale

Curcumin (Cur) exhibits biological activities that support its candidacy for cancer treatment. However, there are limitations to its pharmacological effects, such as poor solubility and bioavailability. Notably, the use of Cur analogs has potential for addressing these limitations. Dehydrozingerone (DZG) is a representative of the half-chemical structure of Cur, and many reports have indicated that it is anticancer in vitro. We, therefore, have hypothesized that DZG could inhibit prostate cancer progression both in vitro and in vivo. Results revealed that DZG decreased cell proliferation of rat castration-resistant prostate cancer, PLS10 cells, via induction of the cell cycle arrest in the G1 phase in vitro. In the PLS10 xenograft model, DZG significantly decreased the growth of subcutaneous tumors when compared to the control via the inhibition of cell proliferation and angiogenesis. To prove that DZG could improve the limitations of Cur, an in vivo pharmacokinetic was determined. DZG was detected in the serum at higher concentrations and remained up to 3 h after intraperitoneal injections, which was longer than Cur. DZG also showed superior in vivo tissue distribution than Cur. The results suggest that DZG could be a candidate of the Cur analog that can potentially exert anticancer capabilities in vivo and thereby improve its bioavailability.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Particle Size; Prostatic Neoplasms; Rats; Styrenes

Dehydrozingerone (DHZ) exerts beneficial effects on human health; however, its mechanism of action remains unclear. Here, we found that DHZ suppressed high-fat diet-induced weight gain, lipid accumulation and hyperglycaemia in C57BL/6 mice and increased AMP-activated protein kinase (AMPK) phosphorylation and stimulated glucose uptake in C2C12 skeletal muscle cells. DHZ activated p38 mitogen-activated protein kinase (MAPK) signalling in an AMPK-dependent manner. Inhibiting AMPK or p38 MAPK blocked DHZ-induced glucose uptake. DHZ increased GLUT4 (major transporter for glucose uptake) expression in skeletal muscle. Glucose clearance and insulin-induced glucose uptake increased in DHZ-fed animals, suggesting that DHZ increases systemic insulin sensitivity in vivo. Thus, the beneficial health effects of DHZ could possibly be explained by its ability to activate the AMPK pathway in skeletal muscle.

Topics: AMP-Activated Protein Kinases; Animals; Biological Transport; Blood Glucose; Cells, Cultured; Curcumin; Deoxyglucose; Diet, High-Fat; Enzyme Activation; Glucose; Glucose Transporter Type 4; Hyperglycemia; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Obesity; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; RNA Interference; RNA, Small Interfering; Styrenes

Protective effects of recently synthesised dehydrozingerone, M1OH (which is one half of the molecule of curcumin) and dimer of dehydrozingerone, D1(OH)2, as individual compounds (1 mM) and as equimolar binary (1:1) and ternary (1:1:1) mixtures with α-tocopherol (TOH) and/or ascorbyl palmitate (AscPH), were studied during bulk lipid autoxidation at 80 °C. The highest oxidation stability of lipid substrate, in the presence of individual compounds, was found for TOH, followed by D1(OH)2 and M1OH, determined from the main kinetic parameters (antioxidant efficiency, reactivity and capacity). AscPH did not show any protective effect. Synergism was obtained for the binary mixtures of (TOH+AscPH) [42.4%], (M1OH+TOH) [32.4%] and (M1OH+AscPH) [35.6%] and for the ternary mixture of (M1OH+TOH+AscPH) [28.7%]. Different protective effects observed were explained on the basis (of results) of TOH regeneration and its content determined by HPLC. These antioxidant binary and ternary mixtures can be used as functional components of foods with health-promoting effects.

Topics: alpha-Tocopherol; Antioxidants; Ascorbic Acid; Curcumin; Lipids; Molecular Structure; Oxidation-Reduction; Styrenes

Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4-6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H2O2, MPP+ and MnCl2 were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.

Topics: Adrenal Gland Neoplasms; alpha-Synuclein; Alzheimer Disease; Animals; Antioxidants; Cell Line, Tumor; Curcumin; Cytoprotection; Guaiacol; Parkinson Disease; Pheochromocytoma; Rats; Styrenes

Effects of curcumin and related compounds on product formation in radiolysis of aerated and deaerated ethanol were studied. Ab initio calculations of enthalpy values relating to O-H bond dissociation and H-atom addition to > C = O bonds of the compounds under study have been performed. The obtained data allowed the conclusion that the presence of a 7-carbon chain containing conjugated > C = C < and > C = O bonds in the structures of curcumin and its analogues makes these compounds capable of inhibiting the reactions involving α-hydroxyl-containing carbon-centered radicals. This finding broadens the existing views concerning radical-regulating properties of curcuminoids, and it should be taken into account when practical use of these compounds is envisaged.

Topics: Acrolein; Aldehydes; Antioxidants; Chalcone; Curcumin; Ethanol; Free Radicals; Guaiacol; Hexanones; Hydrogen; Molecular Structure; Oxygen; Pentanones; Pulse Radiolysis; Structure-Activity Relationship; Styrenes; Thermodynamics

Dehydrozingerone (1) is a pungent constituent present in the rhizomes of ginger (Zingiber officinale) and belongs structurally to the vanillyl ketone class. It is a representative of half the chemical structure of curcumin (2), which is an antioxidative yellow pigment obtained from the rhizomes of turmeric (Curcuma longa). Numerous studies have suggested that 2 is a promising phytochemical for the inhibition of malignant tumors, including colon cancer. On the other hand, there have been few studies on the potential antineoplastic properties of 1, and its mode of action based on a molecular mechanism is little known. Therefore, the antiproliferative effects of 1 were evaluated against HT-29 human colon cancer cells, and it was found that 1 dose-dependently inhibited growth at the G2/M phase with up-regulation of p21. Dehydrozingerone additionally led to the accumulation of intracellular ROS, although most radical scavengers could not clearly repress the cell-cycle arrest at the G2/M phase. Furthermore, two synthetic isomers of 1 (iso-dehydrozingerone, 3, and ortho-dehydrozingerone, 4) were also examined. On comparing of their activities, accumulation of intracellular ROS was found to be interrelated with growth-inhibitory effects. These results suggest that analogues of 1 may be potential chemotherapeutic agents for colon cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Division; Colonic Neoplasms; Curcuma; Curcumin; G2 Phase; HT29 Cells; Humans; Molecular Structure; Reactive Oxygen Species; Stereoisomerism; Styrenes; Zingiberaceae

Dehydrozingerone analogs and related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen activation assay. Among the 40 synthesized compounds, the prenylated analogs 16 and 34-36 showed the most significant and promising activity (100% inhibition of activation at 1 x 10(3) mol ratio/TPA, and 82-80%, 37-35%, and 13-11% inhibition at 5 x 10(2), 1 x 10(2), and 1 x 10 mol ratio/TPA, respectively) in this screening. Their activity profiles were comparable to those of the reference standard curcumin. While a prenyl moiety conferred potent chemopreventive activity, an extended prenyl unit such as a farnesyl moiety did not improve activity. Because in vitro inhibitory effects in this assay generally correlate well with in vivo inhibitory effects on tumor promotion, our results strongly suggested that prenylated 16 and 34-36 are likely to be promising antitumor promoters.

Topics: Anticarcinogenic Agents; Antigens, Viral; Carcinogens; Combinatorial Chemistry Techniques; Curcumin; Molecular Structure; Stereoisomerism; Styrenes; Tetradecanoylphorbol Acetate

Growth factor and oxidative stress-mediated migration and proliferation of vascular smooth muscle cells (VSMCs) play a key role in the pathogenesis of atherosclerosis. The objective of this study was to assess the ability of dehydrozingerone, a structural analog of curcumin, to inhibit PDGF-stimulated vascular functions in VSMCs.. VSMCs isolated from adult rats were treated with dehydrozingerone (0 to 50 microM) before challenge with PDGF (10 ng/mL) and migration, proliferation, and collagen synthesis were assayed by transwell-migration, thymidine-, and L-proline-incorporation assays, respectively. Phosphorylation of PDGF-receptor (PDGFR) and Akt were assessed by Western blotting. Cellular protein tyrosine phosphatase (PTP) activity was determined by the extent of p-nitro-phenyl phosphate hydrolysis.. Dehydrozingerone elicited a concentration-dependent inhibition of PDGF-stimulated VSMC migration, proliferation, collagen synthesis, and PDGF/H2O2-stimulated phosphorylation of PDGFR-beta and downstream Akt. Dehydrozingerone also inhibited H2O2-mediated oxidation of PTP.. Dehydrozingerone is a potent inhibitor of growth factor/ H2O2-stimulated VSMC functions and may play a critical role in regulating these events after vascular injury. Inhibition of oxidation of cellular phosphatases may represent one of the mechanisms by which dehydrozingerone inhibits these VSMC functions. Inability of the structural analog isoeugenol to inhibit PDGF-signaling suggests that the carbonyl side chain may be necessary for activity.

Topics: Animals; Aorta, Thoracic; Cell Movement; Cell Proliferation; Cells, Cultured; Collagen; Curcumin; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Muscle, Smooth, Vascular; Phosphorylation; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Styrenes; Tunica Intima

The low volatility and thermal instability made the photoelectron (PE), electron transmission (ET), and dissociative electron attachment (DEA) spectroscopy measurements on curcumin (a potent chemopreventive agent) unsuccessful. The filled and empty electronic structure of curcumin was therefore investigated by exploiting the PES, ETS, and DEAS results for representative fragment molecules and suitable quantum-mechanical calculations. On this basis, a reliable pattern of the vertical ionization energies and electron attachment energies of curcumin was proposed. The pi frontier molecular orbitals (MOs) are characterized by sizable interaction between the two phenol rings transmitted through the dicarbonyl chain and associated with a remarkably low ionization energy and a negative electron attachment energy (i.e., a largely positive electron affinity), diagnostic of a stable anion state not observable in ETS. The lowest energy electronic transitions of half-curcumin and curcumin and their color change by alkalization were interpreted with time-dependent density functional theory (DFT) calculations. For curcumin, it is shown that loss of a phenolic proton occurs in alkaline ethanolic solution.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcumin; Quantum Theory; Spectrum Analysis; Styrenes

One new quinoline alkaloid and seven known bisabolane sesquiterpenes: 2-(2'-methyl-1'-propenyl)-4, 6-dimethyl-7-hydroxyquinoline (1), 2, 5-dihydroxybisabola-3, 10-diene (2), 4, 5-dihydroxybisabola-2,10-diene (3), turmeronol A (4), bisacurone (5), bisacurone A (6), bisacurone B (7) , bisacurone C (8), as well as dehydrozingerone (9) and zingerone (10) were isolated from the root tuber of Curcuma longa. Their structures were identified by spectral evidence. Compound 1 is a new compound, compounds 6 -8 were isolated from this plant for the first time and compounds 9 - 10 from Curcuma for the first time.

Topics: Alkaloids; Curcuma; Cyclohexanols; Guaiacol; Molecular Structure; Plant Tubers; Plants, Medicinal; Sesquiterpenes; Styrenes

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, and thus, the in vivo imaging of plaques and tangles would be beneficial for the early diagnosis of AD. It has been suggested that 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (curcumin) may be responsible for low age-adjusted prevalence of AD in India. In the present study, eight novel derivatives of curcumin and 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (dehydrozingerone) were synthesized and their binding affinities for beta-amyloid (Abeta) aggregates were measured. Of these ligands, fluoropropyl-substituted curcumin (8) showed the highest binding affinity (Ki=0.07 nM), and therefore, 8 was radiolabeled and evaluated as a potential probe for Abeta plaque imaging. Partition coefficient measurement and biodistribution in normal mice demonstrated that [18F]8 has a suitable lipophilicity and reasonable initial brain uptake. Metabolism studies also indicated that [18F]8 is metabolically stable in the brain. These results suggest that [18F]8 is a suitable radioligand for Abeta plaque imaging.

Topics: Amyloid; Amyloid beta-Peptides; Animals; Brain; Curcumin; Fluorine Radioisotopes; Guaiacol; Isotope Labeling; Ligands; Male; Mice; Mice, Inbred ICR; Positron-Emission Tomography; Radiopharmaceuticals; Styrenes; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

Dehydrozingerone, 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one, is half an analog of curcumin which is known to have anti-tumor activity. The anti-tumor promoting activity of dehydrozingerone was evaluated by determining the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). The concentration needed for 50% inhibition of the tumor promotion (IC50) of dehydrozingerone was similar to that of curcumin. To elucidate the structure-activity relationship on the anti-tumor promoting activity, dehydrozingerone, curcumin, isoeugenol, which has no carbonyl group in the side chain, benzalacetone, which is the basic structure of dehydrozingerone, o-dehydrozingerone, which is the ortho-hydroxyl substituted compound of dehydrozingerone, and their related compounds were investigated using the in vitro short-term assay on TPA-induced EBV-EA activation. o-Dehydrozingerone showed the most potent inhibitory effect in a series of tested dehydrozingerone derivatives and their related monosubstituted benzalacetones. This suggests that the occupation at both ortho positions of the hydroxyl group enhances the anti-tumor promoting activity. Isoeugenol inhibited the tumor promoting activity at a concentration of about one-third of the IC50 of dehydrozingerone. This indicates that the carbonyl group in the side chain has a negative impact on the anti-tumor promoting activity. The inhibitory effects of the carbon-carbon bond in the side chain were studied using benzylacetone with a single bond, benzalacetone with a double bond and 4-phenyl-3-butyn-2-one with a triple bond. 4-Phenyl-3-butyn-2-one inhibited the most potent activity followed by benzalacetone and benzylacetone.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antigens, Viral; Carcinogens; Curcumin; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Inhibitory Concentration 50; Structure-Activity Relationship; Styrenes; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

The present study investigates the inhibition of lipid peroxidation by dehydrozingerone and curcumin in rat brain homogenates. Both the test compounds inhibited the formation of conjugated dienes and spontaneous lipid peroxidation. These compounds also inhibited lipid peroxidation induced by ferrous ions, ferric-ascorbate and ferric-ADP-ascorbate. In all these cases, curcumin was more active than dehydrozingerone and dl-alpha-tocopherol.

Topics: Animals; Antioxidants; Brain; Curcumin; Female; Iron Compounds; Lipid Peroxidation; Male; Rats; Styrenes; Tissue Extracts