Structural Analogue Of Curcumin Research Articles

Identification of curcumin analogues with anti-seizure potential in vivo using chemical and genetic zebrafish larva seizure models

Seizures are the outward manifestation of abnormally excessive or synchronous brain activity. While seizures can be somewhat symptomatically managed with anti-epileptic drugs (AEDs), many patients are still refractory to the currently available AEDs. As a result, there is a need to identify new molecules with anti-seizure properties. Curcumin is the principle curcuminoid of Curcuma longa, or colloquially turmeric, and has been experimentally proven to have anti-convulsive properties, but its poor bioavailability has dampened further therapeutic interest. Hence, this study aimed to ask if structural analogues of curcumin with an adequate bioavailability could have an anti-seizure effect in vivo. To do so, we tested these analogues following a multipronged approach combining the use of several zebrafish seizure models (chemically-induced and genetic) and complementary assays (behavioural and brain activity). Overall, from the 68 analogues tested, we found 15 different derivatives that were able to significantly decrease the behavioural hyperactivity induced by pentylenetetrazol. Of those, only a few showed an effect on the hyperactivity phenotype of two genetic models of brain seizures that are the gabra1 and gabrg2 knockouts. Two analogues, CA 80(1) and CA 74(1), were able to significantly alleviate brain seizures of gabrg2-mutant larvae. As a result, these analogues are good candidates as novel anti-seizure agents.

STUDIES ON BIOAVAILABILITY ENHANCEMENT OF CURCUMIN

Objective: The objective of the present work was to improve aqueous solubility and in vivo bioavailability of curcumin and structural analogues of curcumin such as potassium, calcium, magnesium salts and nitro derivative.
 Methods: Structural analogues of curcumin were prepared by reaction of curcumin with potassium chloride, magnesium chloride hexahydrate and calcium chloride dihydrate in a suitable solvent. The nitro derivative synthesized by treating curcumin with sulphuric acid and nitric acid. The prepared analogues were evaluated for melting behavior, solubility, UV spectrophotometry, partition coefficient, moisture content, cellular uptake, FTIR analysis, antimicrobial activity and in vivo bioavailability in the rat.
 Results: Chemical modification of curcumin increased the saturation solubility to 11.6, 16.5, 21.5, 28.0 µg/ml in calcium salt, magnesium salt, potassium salt and nitro derivative respectively, against 8.6 µg/ml of curcumin. The analogues were chemically stable as curcumin analyzed by FTIR spectrophotometry. Increased cellular uptake, as well as enhanced antimicrobial activity, was demonstrated by modified curcumin analogues. Moreover, significant improvement in plasma levels was estimated with nitro derivative.
 Conclusion: The present work recommends that nitration of curcumin improves aqueous solubility which may improve absorption and in vivo bioavailability.

Voyage into Curcumin Embedded Delivery Systems of Natural Polymers to Ameliorate Solubility and Bioavailability Limitations

The turmeric (Curcuma longa) plant, a perennial herb of the ginger family, is an agronomic crop in south and southeast tropical Asia. The rhizome is coined as the most useful part of the plant and a staple in all cooking and treatment of medicinal purposes include antioxidant, anti-viral, anti-bacterial, anti-fungal, anti-carcinogenic, anti-mutagenic and anti-inflammatory. It has a wide array of affinity to biological proteins and inhibits various kinases. Curcumin modulates the activity of several transcription factors, regulates the functioning of inflammatory enzymes, cytokines, adhesion molecules, and apoptic proteins. Recent preclinical and animal studies revealed the anti-proliferative, anti-invasive and antiangiogenic activity5,6. Clinically, Curcumin is proven to be safe while administering at larger doses, but due to poor aqueous solubility, quick systemic elimination, scanty tissue absorption and degradation at alkaline pH, which restrains its bioavailability, following strategies are used to enhance the bioavailability: (i) adjuvants like piperine which interferes with glucuronidation, (ii) liposomal curcumin, (iii) nanoparticles, (iv) Curcumin phospholipid complex and (v) structural analogues of curcumin. (VI) Micronisation and nanonisation (VII) self-microemulsifying drug delivery systems (SMEDDS), (vii) cyclodextrin inclusions, (IX) solid dispersions (X) Nanoemulsions, nanospheres, nanobeads, nanofibres7. The intention of this comprehension is to present a retrospective and prospective gist of applications of innovative delivery systems of Curcumin employed by the researchers to optimize Curcumin delivery using natural polymers with the objective of enhancing solubility and bioavailability, which might revolutionize the therapy of challenging chronic disorders of mankind.

Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase

Dimethoxycurcumin (DIMC), a structural analogue of curcumin, has been shown to have more stability, bioavailability, and effectiveness than its parent molecule curcumin. In this paper the radiosensitizing effect of DIMC has been investigated in A549 lung cancer cells. As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay. DIMC in combination with radiation significantly increased the apoptosis and mitotic death in A549 cells. This combinatorial treatment also lead to effective elimination of cancer stem cells. Further, there was a significant increase in cellular ROS, decrease in GSH to GSSG ratio and also significant slowdown in DNA repair when DIMC was combined with radiation. In silico docking studies and in vitro studies showed inhibition of thioredoxin reductase enzyme by DIMC. Overexpression of thioredoxin lead to the abrogation of radiosensitizing effect of DIMC underscoring the role of thioredoxin reductase in radiosensitization. Our results clearly demonstrate that DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system.

Protein expression changes induced in a malignant melanoma cell line by the curcumin analogue compound D6.

BackgroundWe have previously demonstrated that the hydroxylated biphenyl compound D6 (3E,3′E)-4,4′-(5,5′,6,6′-tetramethoxy-[1,1′-biphenyl]-3,3′-diyl)bis(but-3-en-2-one), a structural analogue of curcumin, exerts a strong antitumor activity on melanoma cells both in vitro and in vivo. Although the mechanism of action of D6 is yet to be clarified, this compound is thought to inhibit cancer cell growth by arresting the cell cycle in G2/M phase, and to induce apoptosis through the mitochondrial intrinsic pathway. To investigate the changes in protein expression induced by exposure of melanoma cells to D6, a differential proteomic study was carried out on D6-treated and untreated primary melanoma LB24Dagi cells.MethodsProteins were fractionated by SDS-PAGE and subjected to in gel digestion. The peptide mixtures were analyzed by liquid chromatography coupled with tandem mass spectrometry. Proteins were identified and quantified using database search and spectral counting. Proteomic data were finally uploaded into the Ingenuity Pathway Analysis software to find significantly modulated networks and pathways.ResultsAnalysis of the differentially expressed protein profiles revealed the activation of a strong cellular stress response, with overexpression of several HSPs and stimulation of ubiquitin-proteasome pathways. These were accompanied by a decrease of protein synthesis, evidenced by downregulation of proteins involved in mRNA processing and translation. These findings are consistent with our previous results on gene expression profiling in melanoma cells treated with D6.ConclusionsOur findings confirm that the curcumin analogue D6 triggers a strong stress response in melanoma cells, turning down majority of cell functions and finally driving cells to apoptosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2362-6) contains supplementary material, which is available to authorized users.

Molecular changes induced by the curcumin analogue D6 in human melanoma cells

BackgroundIn a previous report, we described the in vitro and in vivo antiproliferative and proapoptotic activity of a hydroxylated biphenyl (D6), a structural analogue of curcumin, on malignant melanoma and neuroblastoma tumours. In this paper, we investigated the molecular changes induced by such a compound, underlying cell growth arrest and apoptosis in melanoma cells.ResultsTo shed light on the mechanisms of action of D6, we firstly demonstrated its quick cellular uptake and subsequent block of cell cycle in G2/M phase transition. A gene expression profile analysis of D6-treated melanoma cells and fibroblasts was then carried out on high density microarrays, to assess gene expression changes induced by this compound. The expression profile study evidenced both an induction of stress response pathways and a modulation of cell growth regulation mechanisms. In particular, our data suggest that the antiproliferative and proapoptotic activities of D6 in melanoma could be partially driven by up-regulation of the p53 signalling pathways as well as by down-regulation of the PI3K/Akt and NF-kB pathways. Modulation of gene expression due to D6 treatment was verified by western blot analysis for single proteins of interest, confirming the results from the gene expression profile analysis.ConclusionsOur findings contribute to the understanding of the mechanisms of action of D6, through a comprehensive description of the molecular changes induced by this compound at the gene expression level, in agreement with the previously reported anti-tumour effects on melanoma cells.

Dehydrozingerone, a Structural Analogue of Curcumin, Induces Cell-Cycle Arrest at the G2/M Phase and Accumulates Intracellular ROS in HT-29 Human Colon Cancer Cells

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.

Abstract 3804: Molecular changes induced by the curcumin biphenyl analogue D6 in melanoma cells

Abstract Malignant melanoma (MM) is one of the most aggressive cancers that affect humans. It is the most common and fatal skin cancer, with an incidence that is critically increasing in Western populations (15 times in the last 40 years) and for which, in the advanced stages, there is no effective therapy. The search for new compounds able to control it is therefore essential. The hydroxylated biphenyl compound (3E,3′E)-4,4′-(5,5′,6,6′-tetramethoxy-[1,1′-biphenyl]-3,3′-diyl)bis(but-3-en-2-one), namely D6, a structural analogue of curcumin, showed a strong antitumor activity on MM cells both in vitro and in vivo, as we have recently described [1]. The mechanisms of action of this compound are not clear yet, but it inhibits cancer cells growth by inducing apoptosis without affecting normal fibroblasts growth. Firstly we investigated the ability of D6 to enter cells by Liquid Chromatography-Mass Spectrometry (LC-MS) analysis. The LC-MS data showed a quick cellular uptake of D6 with a maximum peak after about 2 hours. To investigate on the effects of D6 treatment on the cell cycle progression in MM cells, we performed flow cytometry analysis, which evidenced a cell cycle arrest in the G2/M phase. Gene expression profiles analysis using Illumina® high-density microarrays, was carried out on D6 treated MM cells and normal fibroblasts allowing the identification of 599 transcripts whose expression was modulated by D6 treatment in MM cells but not in normal fibroblast. The analysis of results, performed by Ingenuity Pathway Analysis software, showed the centrality of CDKN1A gene, encoding p21, a major negative cell cycle regulator, which was strongly over expressed, while cyclin B and cdc25 phosphatase, showed both to be down modulated. Other genes which expression interestingly appeared to be decreased by D6 activity were the oncogenes c-kit and PI3K, suggesting a down regulation of both c-kit mediated and PI3K/AKT signal transduction pathways driving to cell proliferation. Modulation of expression of these specific genes has been confirmed at a protein level by western blotting analysis. Moreover our results pointed out an upregulation of several heat shock family genes, which is probably due to a curcumin related anti inflammatory effect of D6. The preliminary results of these analysis show that D6 induces molecular changes in MM cells at both gene expression and protein levels, involving major cell proliferation regulatory pathways. [1] Marina Pisano et al. (2010).Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells. Molecular Cancer, 9:137. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3804. doi:1538-7445.AM2012-3804

Dimethoxycurcumin, a Structural Analogue of Curcumin, Induces Apoptosis in Human Renal Carcinoma Caki Cells Through the Production of Reactive Oxygen Species, the Release of Cytochrome c, and the Activation of Caspase-3

PurposeCurcumin (Cur) has been reported to induce apoptosis in human renal carcinoma Caki cells. Dimethoxycurcumin (DMC), one of several synthetic Cur analogues, has been reported to have increased metabolic stability over Cur. We determined whether DMC, like Cur, induces apoptosis in Caki cells and also compared the apoptosis-inducing activity of DMC with that of Cur.Materials and MethodsCaki cells were treated with DMC possessing four methoxy groups, Cur possessing two methoxy groups, or bis-demethoxycurcumin (BMC), which lacks a methoxy group. Cell viability was measured by using a methyltetrazolium assay. Flow cytometry and the caspase-3 activity assay were used to detect apoptosis. The release of cytochrome-c (Cyt c) was detected by Western blot analysis. The production of reactive oxygen species (ROS) was measured by flow cytometry.ResultsDMC, Cur, and BMC reduced cell viability and induced apoptosis, but the potency varied; DMC was the most potent compound, followed by Cur and BMC. ROS production, Cyt c release, and caspase-3 activity were increased, again in the order DMC>Cur>BMC. N-Acetylcysteine, a potent antioxidant, inhibited ROS production, Cyt c release, caspase-3 activation, and apoptosis induction in DMC-treated cells.ConclusionsThese results indicate that DMC, like the original form of Cur, may induce apoptosis in human renal carcinoma Caki cells through the production of ROS, the release of mitochondrial Cyt c, and the subsequent activation of caspase-3. In addition, DMC is more potent than Cur in the ability to induce apoptosis.